Pyrazole compounds useful as protein kinase inhibitors

ABSTRACT

This invention describes novel pyrazole compounds of formula IIa:                    
     wherein R 1  is T-Ring D, wherein Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl; R x  and R y  are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 heteroatoms; and R 2  and R 2  are as described in the specification. The compounds are useful as protein kinase inhibitors, especially as inhibitors of Aurora-2 and GSK-3, for treating diseases such as cancer, diabetes and Alzheimer&#39;s disease.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Pat. App. No.60/257,887 filed Dec. 21, 2000 and U.S. Provisional Pat. App. No.60/286,949 filed Apr. 27, 2001, the contents of which are incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention is in the field of medicinal chemistry and relatesto compounds that are protein kinase inhibitors, compositions containingsuch compounds and methods of use. More particularly, this inventionrelates to compounds that are inhibitors of Aurora-2 protein kinase. Theinvention also relates to methods of treating diseases associated withprotein kinases, especially diseases associated with Aurora-2, such ascancer.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by better understanding of the structure of enzymes and otherbiomolecules associated with target diseases. One important class ofenzymes that has been the subject of extensive study is the proteinkinases.

Protein kinases mediate intracellular signal transduction. They do thisby effecting a phosphoryl transfer from a nucleoside triphosphate to aprotein acceptor that is involved in a signaling pathway. There are anumber of kinases and pathways through which extracellular and otherstimuli cause a variety of cellular responses to occur inside the cell.Examples of such stimuli include environmental and chemical stresssignals (e.g. osmotic shock, heat shock, ultraviolet radiation,bacterial endotoxin, H₂O₂), cytokines (e.g. interleukin-1 (IL-1) andtumor necrosis factor α (TNF-α)), and growth factors (e.g. granulocytemacrophage-colony-stimulating factor (GM-CSF), and fibroblast growthfactor (FGF). An extracellular stimulus may effect one or more cellularresponses related to cell growth, migration, differentiation, secretionof hormones, activation of transcription factors, muscle contraction,glucose metabolism, control of protein synthesis and regulation of cellcycle.

Many diseases are associated with abnormal cellular responses triggeredby protein kinase-mediated events. These diseases include autoimmunediseases, inflammatory diseases, neurological and neurodegenerativediseases, cancer, cardiovascular diseases, allergies and asthma,Alzheimer's disease or hormone-related diseases. Accordingly, there hasbeen a substantial effort in medicinal chemistry to find protein kinaseinhibitors that are effective as therapeutic agents.

Aurora-2 is a serine/threonine protein kinase that has been implicatedin human cancer, such as colon, breast and other solid tumors. Thiskinase is believed to be involved in protein phosphorylation events thatregulate the cell cycle. Specifically, Aurora-2 may play a role incontrolling the accurate segregation of chromosomes during mitosis.Misregulation of the cell cycle can lead to cellular proliferation andother abnormalities. In human colon cancer tissue, the aurora-2 proteinhas been found to be overexpressed. See Bischoff et al., EMBO J., 1998,17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646;Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinasecomprised of α and β isoforms that are each encoded by distinct genes[Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim and Kimmel,Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK-3 has beenimplicated in various diseases including diabetes, Alzheimer's disease,CNS disorders such as manic depressive disorder and neurodegenerativediseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; andHaq et al., J. Cell Biol. (2000) 151, 117]. These diseases may be causedby, or result in, the abnormal operation of certain cell signalingpathways in which GSK-3 plays a role. GSK-3 has been found tophosphorylate and modulate the activity of a number of regulatoryproteins. These proteins include glycogen synthase which is the ratelimiting enzyme necessary for glycogen synthesis, the microtubuleassociated protein Tau, the gene transcription factor β-catenin, thetranslation initiation factor e1F2B, as well as ATP citrate lyase, axin,heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBα. These diverseprotein targets implicate GSK-3 in many aspects of cellular metabolism,proliferation, differentiation and development.

In a GSK-3 mediated pathway that is relevant for the treatment of typeII diabetes, insulin-induced signaling leads to cellular glucose uptakeand glycogen synthesis. Along this pathway, GSK-3 is a negativeregulator of the insulin-induced signal. Normally, the presence ofinsulin causes inhibition of GSK-3 mediated phosphorylation anddeactivation of glycogen synthase. The inhibition of GSK-3 leads toincreased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93,8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen,Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J.299, 123-128 (1994)]. However, in a diabetic patient where the insulinresponse is impaired, glycogen synthesis and glucose uptake fail toincrease despite the presence of relatively high blood levels ofinsulin. This leads to abnormally high blood levels of glucose withacute and long term effects that may ultimately result in cardiovasculardisease, renal failure and blindness. In such patients, the normalinsulin-induced inhibition of GSK-3 fails to occur. It has also beenreported that in patients with type II diabetes, GSK-3 is overexpressed[WO 00/38675]. Therapeutic inhibitors of GSK-3 therefore are consideredto be useful for treating diabetic patients suffering from an impairedresponse to insulin.

GSK-3 activity has also been associated with Alzheimer's disease. Thisdisease is characterized by the well-known β-amyloid peptide and theformation of intracellular neurofibrillary tangles. The neurofibrillarytangles contain hyperphosphorylated Tau protein where Tau isphosphorylated on abnormal sites. GSK-3 has been shown to phosphorylatethese abnormal sites in cell and animal models. Furthermore, inhibitionof GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells[Lovestone et al., Current Biology 4, 1077-86 (1994); Brownlees et al.,Neuroreport 8, 3251-55 (1997)]. Therefore, it is believed that GSK-3activity may promote generation of the neurofibrillary tangles and theprogression of Alzheimer's disease.

Another substrate of GSK-3 is β-catenin which is degradated afterphosphorylation by GSK-3. Reduced levels of β-catenin have been reportedin schizophrenic patients and have also been associated with otherdiseases related to increase in neuronal cell death [Zhong et al.,Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993);Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997)].

As a result of the biological importance of GSK-3, there is currentinterest in therapeutically effective GSK-3 inhbitors. Small moleculesthat inhibit GSK-3 have recently been reported [WO 99/65897 (Chiron) andWO 00/38675 (SmithKline Beecham)].

For many of the aforementioned diseases associated with abnormal GSK-3activity, other protein kinases have also been targeted for treating thesame diseases. However, the various protein kinases often act throughdifferent biological pathways. For example, certain quinazolinederivatives have been reported recently as inhibitors of p38 kinase (WO00/12497 to Scios). The compounds are reported to be useful for treatingconditions characterized by enhanced p38-α0 activity and/or enhancedTGF-β activity. While p38 activity has been implicated in a wide varietyof diseases, including diabetes, p38 kinase is not reported to be aconstituent of an insulin signaling pathway that regulates glycogensynthesis or glucose uptake. Therefore, unlike GSK-3, p38 inhibitionwould not be expected to enhance glycogen synthesis and/or glucoseuptake.

There is a continued need to find new therapeutic agents to treat humandiseases. The protein kinases Aurora-2 and GSK-3 are especiallyattractive targets for the discovery of new therapeutics due to theirimportant roles in cancer and diabetes, respectively.

DESCRIPTION OF THE INVENTION

It has now been found that compounds of this invention andpharmaceutical compositions thereof are effective as protein kinaseinhibitors, particularly as inhibitors of Aurora-2. These compounds havethe general formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z¹ is nitrogen or C—R⁸ and Z² is nitrogen or CH, wherein at least one ofZ¹ and Z² is nitrogen;

R^(x) and R^(y) are independently selected from T—R³ or L—Z—R³, or R^(x)and R^(y) are taken together with their intervening atoms to form afused, unsaturated or partially unsaturated, 5-7 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereineach substitutable ring carbon of said fused ring formed by R^(x) andR^(y) is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

Q is selected from —N(R⁴)—, —O—, —S—, —C(R^(6′))₂—,1,2-cyclopropanediyl, 1,2-cyclobutanediyl, or 1,3-cyclobutanediyl;

R¹ is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbonof Ring D is independently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q is—C(R^(6′))₂—, a methylene unit of said C₁₋₄ alkylidene chain isoptionally replaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—, —SO₂—,—SO₂NH—, —NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;

Z is a C₁₋₄ alkylidene chain;

L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

R² and R_(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R² isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom may be taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R^(6′) is independently selected from hydrogen or a C₁₋₄ aliphaticgroup, or two R^(6′) on the same carbon atom are taken together to forma 3-6 membered carbocyclic ring;

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂.

As used herein, the following definitions shall apply unless otherwiseindicated. The phrase “optionally substituted” is used interchangeablywith the phrase “substituted or unsubstituted” or with the term“(un)substituted.” Unless otherwise indicated, an optionally substitutedgroup may have a substituent at each substitutable position of thegroup, and each substitution is independent of the other.

The term “aliphatic” as used herein means straight-chain, branched orcyclic C₁-C₁₂ hydrocarbons which are completely saturated or whichcontain one or more units of unsaturation but which are not aromatic.For example, suitable aliphatic groups include substituted orunsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl. The terms “alkyl”, “alkoxy”, “hydroxyalkyl”,“alkoxyalkyl”, and “alkoxycarbonyl”, used alone or as part of a largermoiety includes both straight and branched chains containing one totwelve carbon atoms. The terms “alkenyl” and “alkynyl” used alone or aspart of a larger moiety shall include both straight and branched chainscontaining two to twelve carbon atoms. The term “cycloalkyl” used aloneor as part of a larger moiety shall include cyclic C₃-C₁₂ hydrocarbonswhich are completely saturated or which contain one or more units ofunsaturation, but which are not aromatic.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl,alkenyl or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “heteroatom” means nitrogen, oxygen, or sulfur and includes anyoxidized form of nitrogen and sulfur, and the quaternized form of anybasic nitrogen. Also the term “nitrogen” includes a substitutablenitrogen of a heterocyclic ring. As an example, in a saturated orpartially unsaturated ring having 0-3 heteroatoms selected from oxygen,sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl).

The terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” asused herein means an aliphatic ring system having three to fourteenmembers. The terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or“carbocyclic” whether saturated or partially unsaturated, also refers torings that are optionally substituted. The terms “carbocycle”,“carbocyclyl”, “carbocyclo”, or “carbocyclic” also include aliphaticrings that are fused to one or more aromatic or nonaromatic rings, suchas in a decahydronaphthyl or tetrahydronaphthyl, where the radical orpoint of attachment is on the aliphatic ring.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to aromatic ring groupshaving five to fourteen members, such as phenyl, benzyl, phenethyl,1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. The term “aryl”also refers to rings that are optionally substituted. The term “aryl”may be used interchangeably with the term “aryl ring”. “Aryl” alsoincludes fused polycyclic aromatic ring systems in which an aromaticring is fused to one or more rings. Examples include 1-naphthyl,2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scopeof the term “aryl”, as it is used herein, is a group in which anaromatic ring is fused to one or more non-aromatic rings, such as in anindanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical orpoint of attachment is on the aromatic ring.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinincludes non-aromatic ring systems having five to fourteen members,preferably five to ten, in which one or more ring carbons, preferablyone to four, are each replaced by a heteroatom such as N, O, or S.Examples of heterocyclic rings include 3-1H-benzimidazol-2-one,(1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl,4-tetrahydropyranyl, [1,3]-dioxalanyl, [1,3]-dithiolanyl,[1,3]-dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl,3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl,diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl,benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, andbenzothianyl. Also included within the scope of the term “heterocyclyl”or “heterocyclic”, as it is used herein, is a group in which anon-aromatic heteroatom-containing ring is fused to one or more aromaticor non-aromatic rings, such as in an indolinyl, chromanyl,phenanthridinyl, or tetrahydroquinolinyl, where the radical or point ofattachment is on the non-aromatic heteroatom-containing ring. The term“heterocycle”, “heterocyclyl”, or “heterocyclic” whether saturated orpartially unsaturated, also refers to rings that are optionallysubstituted.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to heteroaromatic ringgroups having five to fourteen members. Examples of heteroaryl ringsinclude 2-furanyl, 3-furanyl, 3-furazanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 2-pyrazolyl,3-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl,carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl,quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl,benzimidazolyl, isoquinolinyl, indazolyl, isoindolyl, acridinyl, orbenzoisoxazolyl. Also included within the scope of the term“heteroaryl”, as it is used herein, is a group in which a heteroatomicring is fused to one or more aromatic or nonaromatic rings where theradical or point of attachment is on the heteroaromatic ring. Examplesinclude tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[3,4-d]pyrimidinyl. The term “heteroaryl” also refers to ringsthat are optionally substituted. The term “heteroaryl” may be usedinterchangeably with the term “heteroaryl ring” or the term“heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents. Examples of suitablesubstituents on the unsaturated carbon atom of an aryl, heteroaryl,aralkyl, or heteroaralkyl group include a halogen, —R°, —OR°, —SR°,1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy),phenyl (Ph), substituted Ph, —O(Ph), substituted —O(Ph), —CH₂(Ph),substituted —CH₂(Ph), —CH₂CH₂(Ph), substituted —CH₂CH₂(Ph), —NO₂, —CN,—N(R°)₂, —NR°C(O)R°, —NR°C(O)N(R°)₂, —NR°CO₂R°, —NR°NR°C(O)R°,—NR°NR°C(O)N(R°)₂, —NR°NR°CO₂R°, —C(O)C(O)R°, —C(O)CH₂C(O)R°, —CO₂R°,—C(O)R°, —C(O)N(R°)₂, —OC(O)N(R°)₂, —S(O)₂R°, —SO₂N(R°)₂, —S(O)R°,—NR°SO₂N(R°)₂, —NR°SO₂R°, —C(═S)N(R°)₂, —C(═NH)—N(R°)₂,—(CH₂)_(y)NHC(O)R°, —(CH₂)_(y)NHC(O)CH(V—R°)(R°); wherein each R° isindependently selected from hydrogen, a substituted or unsubstitutedaliphatic group, an unsubstituted heteroaryl or heterocyclic ring,phenyl (Ph), substituted Ph, —O(Ph), substituted —O(Ph), —CH₂(Ph), orsubstituted —CH₂(Ph); y is 0-6; and V is a linker group. Examples ofsubstituents on the aliphatic group or the phenyl ring of R° includeamino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy,dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl,alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

An aliphatic group or a non-aromatic heterocyclic ring may contain oneor more substituents. Examples of suitable substituents on the saturatedcarbon of an aliphatic group or of a non-aromatic heterocyclic ringinclude those listed above for the unsaturated carbon of an aryl orheteroaryl group and the following: ═O, ═S, ═NNHR*, ═NN(R*)₂, ═N—,═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* isindependently selected from hydrogen, an unsubstituted aliphatic groupor a substituted aliphatic group. Examples of substituents on thealiphatic group include amino, alkylamino, dialkylamino, aminocarbonyl,halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano,carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, orhaloalkyl.

Suitable substituents on the nitrogen of a non-aromatic heterocyclicring include —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺,—SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, and —NR⁺SO₂R⁺; whereineach R⁺ is independently selected from hydrogen, an aliphatic group, asubstituted aliphatic group, phenyl (Ph), substituted Ph, —O(Ph),substituted —O(Ph), CH₂(Ph), substituted CH₂(Ph), or an unsubstitutedheteroaryl or heterocyclic ring. Examples of substituents on thealiphatic group or the phenyl ring include amino, alkylamino,dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy,haloalkoxy, or haloalkyl.

The term “linker group” or “linker” means an organic moiety thatconnects two parts of a compound. Linkers are typically comprised of anatom such as oxygen or sulfur, a unit such as —NH—, —CH₂—, —C(O)—,—C(O)NH—, or a chain of atoms, such as an alkylidene chain. Themolecular mass of a linker is typically in the range of about 14 to 200,preferably in the range of 14 to 96 with a length of up to about sixatoms. Examples of linkers include a saturated or unsaturated C₁₋₆alkylidene chain which is optionally substituted, and wherein one or twosaturated carbons of the chain are optionally replaced by —C(O)—,—C(O)C(O)—, —CONH—, —CONHNH—, —CO₂—, —OC(O)—, —NHCO₂—, —O—, —NHCONH—,—OC(O)NH—, —NHNH—, —NHCO—, —S—, —SO—, —SO₂—, —NH—, —SO₂NH—, or —NHSO₂—.

The term “alkylidene chain” refers to an optionally substituted,straight or branched carbon chain that may be fully saturated or haveone or more units of unsaturation. The optional substituents are asdescribed above for an aliphatic group.

A combination of substituents or variables is permissible only if such acombination results in a stable or chemically feasible compound. Astable compound or chemically feasible compound is one in which thechemical structure is not substantially altered when kept at atemperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

Compounds of formula I or salts thereof may be formulated intocompositions. In a preferred embodiment, the composition is apharmaceutical composition. In one embodiment, the composition comprisesan amount of the protein kinase inhibitor effective to inhibit a proteinkinase, particularly Aurora-2, in a biological sample or in a patient.Compounds of this invention and pharmaceutical compositions thereof,which comprise an amount of the protein kinase inhibitor effective totreat or prevent an Aurora-2-mediated condition and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle, may be formulated foradministration to a patient.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formula Ior a pharmaceutical composition thereof.

The term “Aurora-2-mediated disease” or “Aurora-2-mediated condition”,as used herein, means any disease or other deleterious condition inwhich Aurora is known to play a role. The terms “Aurora-2-mediateddisease” or “Aurora-2-mediated condition” also mean those diseases orconditions that are alleviated by treatment with an Aurora-2 inhibitor.Such conditions include, without limitation, colon, breast, stomach, andovarian cancer.

Another aspect of the invention relates to inhibiting Aurora-2 activityin a biological sample, which method comprises contacting the biologicalsample with the Aurora-2 inhibitor of formula I, or a compositionthereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula I or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

The terms “GSK-3-mediated disease” or “GSK-3-mediated condition”, asused herein, mean any disease or other deleterious condition or state inwhich GSK-3 is known to play a role. Such diseases or conditionsinclude, without limitation, diabetes, Alzheimer's disease, Huntington'sDisease, Parkinson's Disease, AIDS-associated dementia, amyotrophiclateral sclerosis (AML), multiple sclerosis (MS), schizophrenia,cardiomycete hypertrophy, reperfusion/ischemia, and baldness.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of the invention relates to inhibiting GSK-3 activity ina biological sample, which method comprises contacting the biologicalsample with a GSK-3 inhibitor of formula I.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula I or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a CDK-2-mediated disease with a CDK-2 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

The terms “CDK-2-mediated disease” or “CDK-2-mediated condition”, asused herein, mean any disease or other deleterious condition in whichCDK-2 is known to play a role. The terms “CDK-2-mediated disease” or“CDK-2-mediated condition” also mean those diseases or conditions thatare alleviated by treatment with a CDK-2 inhibitor. Such conditionsinclude, without limitation, cancer, Alzheimer's disease, restenosis,angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes,psoriasis, atherosclerosis, alopecia, and autoimmune diseases such asrheumatoid arthritis. See Fischer, P. M. and Lane, D. P., CurrentMedicinal Chemistry, 7, 1213-1245 (2000); Mani, S., Wang, C., Wu, K.,Francis, R. and Pestell, R., Exp. Opin. Invest. Drugs, 9, 1849 (2000);Fry, D. W. and Garrett, M. D., Current Opinion in Oncologic, Endocrine &Metabolic Investigational Drugs, 2, 40-59 (2000).

Another aspect of the invention relates to inhibiting CDK-2 activity ina biological sample or a patient, which method comprises administeringto the patient a compound of formula I or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing an ERK-2-mediated diseases with an ERK-2 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

The terms “ERK-mediated disease” or “ERK-mediated condition”, as usedherein mean any disease or other deleterious condition in which ERK isknown to play a role. The terms “ERK-2-mediated disease” or“ERK-2-mediated condition” also mean those diseases or conditions thatare alleviated by treatment with a ERK-2 inhibitor. Such conditionsinclude, without limitation, cancer, stroke, diabetes, hepatomegaly,cardiovascular disease including cardiomegaly, Alzheimer's disease,cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis,restenosis, psoriasis, allergic disorders including asthma,inflammation, neurological disorders and hormone-related diseases. Theterm “cancer” includes, but is not limited to the following cancers:breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus,larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma,lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma,lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma,thyroid, follicular carcinoma, undifferentiated carcinoma, papillarycarcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, livercarcinoma and biliary passages, kidney carcinoma, myeloid disorders,lymphoid disorders, Hodgkin's, hairy cells, buccal cavity and pharynx(oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum,large intestine, rectum, brain and central nervous system, and leukemia.ERK-2 protein kinase and its implication in various diseases has beendescribed [Bokemeyer et al. 1996, Kidney Int. 49, 1187; Anderson et al.,1990, Nature 343, 651; crews et al., 1992, Science 258, 478; Bjorbaek etal., 1995, J. Biol. Chem. 270, 18848; Rouse et al., 1994, Cell 78, 1027;Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247; Raingeaud et al. 1996;Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952; Oliver et al.,1995, Proc. Soc. Exp. Biol. Med. 210, 162; Moodie et al., 1993, Science260, 1658; Frey and Mulder, 1997, Cancer Res. 57, 628; Sivaraman et al.,1997, J Clin. Invest. 99, 1478; Whelchel et al., 1997, Am. J. Respir.Cell Mol. Biol. 16, 589].

Another aspect of the invention relates to inhibiting ERK-2 activity ina biological sample or a patient, which method comprises administeringto the patient a compound of formula I or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing an AKT-mediated diseases with an AKT inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

The terms “AKT-mediated disease” or “AKT-mediated condition”, as usedherein, mean any disease or other deleterious condition in which AKT isknown to play a role. The terms “AKT-mediated disease” or “AKT-mediatedcondition” also mean those diseases or conditions that are alleviated bytreatment with a AKT inhibitor. AKT-mediated diseases or conditionsinclude, but are not limited to, proliferative disorders, cancer, andneurodegenerative disorders. The association of AKT, also known asprotein kinase B, with various diseases has been described [Khwaja, A.,Nature, pp. 33-34, 1990; Zang, Q. Y.; et al, Oncogene, 19 2000;Kazuhiko, N., et al, The Journal of Neuroscience, 20 2000].

Another aspect of the invention relates to inhibiting AKT activity in abiological sample or a patient, which method comprises administering tothe patient a compound of formula I or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a Src-mediated disease with a Src inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

The terms “Src-mediated disease” or “Src-mediated condition”, as usedherein mean any disease or other deleterious condition in which Src isknown to play a role. The terms “Src-mediated disease” or “Src-mediatedcondition” also mean those diseases or conditions that are alleviated bytreatment with a Src inhibitor. Such conditions include, withoutlimitation, hypercalcemia, osteoporosis, osteoarthritis, cancer,symptomatic treatment of bone metastasis, and Paget's disease. Srcprotein kinase and its implication in various diseases has beendescribed [Soriano, Cell, 69, 551 (1992); Soriano et al., Cell, 64, 693(1991); Takayanagi, J. Clin. Invest., 104, 137 (1999); Boschelli, Drugsof the Future 2000, 25(7), 717, (2000); Talamonti, J. Clin. Invest., 91,53 (1993); Lutz, Biochem. Biophys. Res. 243, 503 (1998); Rosen, J. Biol.Chem., 261, 13754 (1986); Bolen, Proc. Natl. Acad. Sci. USA, 84, 2251(1987); Masaki, Hepatology, 27, 1257 (1998); Biscardi, Adv. Cancer Res.,76, 61 (1999); Lynch, Leukemia, 7, 1416 (1993); Wiener, Clin. CancerRes., 5, 2164 (1999); Staley, Cell Growth Diff., 8, 269 (1997)].

Another aspect of the invention relates to inhibiting Src activity in abiological sample or a patient, which method comprises administering tothe patient a compound of formula I or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing an Lck-mediated diseases with an Lck inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

The terms “Lck-mediated disease” or “Lck-mediated condition”, as usedherein, mean any disease state or other deleterious condition in whichLck is known to play a role. The terms “Lck-mediated disease” or“Lck-mediated condition” also mean those diseases or conditions that arealleviated by treatment with an Lck inhibitor. Lck-mediated diseases orconditions include, but are not limited to, autoimmune diseases such astransplant rejection, allergies, rheumatoid arthritis, and leukemia. Theassociation of Lck with various diseases has been described [Molina etal., Nature, 357, 161 (1992)].

Another aspect of the invention relates to inhibiting Lck activity in abiological sample or a patient, which method comprises administering tothe patient a compound of formula I or a composition comprising saidcompound.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that may beadministered to a patient, together with a compound of this invention,and which does not destroy the pharmacological activity thereof.

The term “patient” includes human and veterinary subjects.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; preparations of an enzymesuitable for in vitro assay; biopsied material obtained from a mammal orextracts thereof; and blood, saliva, urine, feces, semen, tears, orother body fluids or extracts thereof.

An amount effective to inhibit protein kinase, for example, Aurora-2 andGSK-3, is an amount that causes measurable inhibition of the kinaseactivity when compared to the activity of the enzyme in the absence ofan inhibitor. Any method may be used to determine inhibition, such as,for example, the Biological Testing Examples described below.

Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions are generally known in the art. Theyinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

In addition to the compounds of this invention, pharmaceuticallyacceptable derivatives or prodrugs of the compounds of this inventionmay also be employed in compositions to treat or prevent theabove-identified diseases or disorders.

A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester or otherderivative of a compound of this invention which, upon administration toa recipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. Particularly favored derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

Pharmaceutically acceptable prodrugs of the compounds of this inventioninclude, without limitation, the following derivatives of the presentcompounds: esters, amino acid esters, phosphate esters, metal saltssulfonate esters, carbamates, and amides.

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acid salts includeacetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

Salts derived from appropriate bases include alkali metal (e.g., sodiumand potassium), alkaline earth metal (e.g., magnesium), ammonium andN⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions the quaternizationof any basic nitrogen-containing groups of the compounds disclosedherein. Water or oil-soluble or dispersible products may be obtained bysuch quaternization.

The amount of the protein kinase inhibitor that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the patient treated and the particular mode of administration.Preferably, the compositions should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of the inhibitor can beadministered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a varietyof-factors, including the activity of the specific compound employed,the age, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of the inhibitor will also depend upon the particular compound inthe composition.

Depending upon the particular protein kinase-mediated condition to betreated or prevented, additional therapeutic agents, which are normallyadministered to treat or prevent that condition, may be administeredtogether with the inhibitors of this invention. For example, in thetreatment of cancer other chemotherapeutic agents or otheranti-proliferative agents may be combined with the present compounds totreat cancer. These agents include, without limitation, adriamycin,dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan,taxol, interferons, and platinum derivatives.

Other examples of agents the inhibitors of this invention may also becombined with include, without limitation, agents for treating diabetessuch as insulin or insulin analogues, in injectable or inhalation form,glitazones, alpha glucosidase inhibitors, biguanides, insulinsensitizers, and sulfonyl ureas; anti-inflammatory agents such ascorticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide,and sulfasalazine; immunomodulatory and immunosuppressive agents such ascyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; and agentsfor treating immunodeficiency disorders such as gamma globulin.

Those additional agents may be administered separately from the proteinkinase inhibitor-containing composition, as part of a multiple dosageregimen. Alternatively, those agents may be part of a single dosageform, mixed together with the protein kinase inhibitor of this inventionin a single composition.

Compounds of this invention may exist in alternative tautomeric forms,as in tautomers i and ii shown below. Unless otherwise indicated, therepresentation of either tautomer is meant to include the other.

R^(x) and R^(y) may be taken together to form a fused ring, providing abicyclic ring system containing Ring A. Preferred R^(x)/R^(y) ringsinclude a 5-, 6-, or 7-membered unsaturated or partially unsaturatedring having 0-2 heteroatoms, wherein said R^(x)/R^(y) ring is optionallysubstituted. Examples of bicyclic systems containing Ring A are shownbelow by compounds I-A through I-BB, wherein Z¹ is nitrogen or C(R⁸) andZ² is nitrogen or C(H).

Preferred bicyclic Ring A systems include I-A, I-B, I-C, I-D, I-E, I-F,I-I, I-J, I-K, I-P, I-Q, I-V, and I-U, more preferably I-A, I-B, I-D,I-E, I-J, I-P, and I-V, and most preferably I-A, I-B, I-D, I-E and I-J.

In the monocyclic Ring A system, preferred R^(x) groups, when present,include hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄ aliphaticgroup such as methyl, ethyl, cyclopropyl, or isopropyl. Preferred R^(y)groups, when present, include T—R³ or L—Z—R³ wherein T is a valence bondor a methylene, L is —O—, —S—, —C(R⁶)₂O—, —CO— or —N(R⁴)—, and R³ is —R,—N(R⁴)₂, or —OR. Preferred R^(y) groups include 5-6 membered heteroarylor heterocyclyl rings, such as 2-pyridyl, 4-pyridyl, pyrrolidinyl,piperidinyl, morpholinyl, or piperazinyl; C₁₋₆ aliphatic, such asmethyl, ethyl, cyclopropyl, isopropyl, or t-butyl; alkoxyalkylamino suchas methoxyethylamino;, alkoxyalkyl such as methoxymethyl ormethoxyethyl; alkyl- or dialkylamino such as ethylamino ordimethylamino; alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy; acetamido; and optionally substituted phenylsuch as phenyl or halo-substituted phenyl.

In the bicyclic Ring A system, the ring formed when R^(x) and R^(y) aretaken together may be substituted or unsubstituted. Suitablesubstituents include —R, halo, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR,—N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂, —N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC C(═O)N(R⁴)₂, wherein R and R⁴ are as defined above.Preferred R^(x)/R^(y) ring substituents include —halo, —R, —OR, —COR,—CO₂R, —CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —NO₂ —N(R⁴)₂,—NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group.

R² and R^(2′) may be taken together to form a fused ring, thus providinga bicyclic ring system containing a pyrazole ring. Preferred fused ringsinclude benzo, pyrido, pyrimido, and a partially unsaturated 6-memberedcarbocyclo ring, wherein said fused ring is optionally substituted.These are exemplified in the following formula I compounds having apyrazole-containing bicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring include one or moreof the following: —halo, —N(R⁴)₂, —C₁₋₃ alkyl, —C₁₋₃ haloalkyl, —NO₂,—O(C₁₋₃ alkyl), —CO₂(C₁₋₃ alkyl), —CN, —SO₂(C₁₋₃ alkyl), —SO₂NH₂,—OC(O)NH₂, —NH₂SO₂(C₁₋₃ alkyl), —NHC(O)(C₁₋₃ alkyl), —C(O)NH₂, and—CO(C₁₋₃ alkyl), wherein the (C₁₋₃ alkyl) is most preferably methyl.

When the pyrazole ring system is monocyclic, preferred R² groups includehydrogen, C₁₋₄ aliphatic, alkoxycarbonyl, (un)substituted phenyl,hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and(N-heterocyclyl)carbonyl. Examples of such preferred R² substituentsinclude methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl,cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH,CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃,CONHCH(CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph,CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂,CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl),CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH,CONH₂, and CO(piperidin-1-yl). A preferred R^(2′) group is hydrogen.

An embodiment that is particularly useful for treating Aurora-2-mediateddiseases relates to compounds of formula IIa:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein;

R^(x) and R^(y) are taken together with their intervening atoms to forma fused, unsaturated or partially unsaturated, 5-7 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereineach substitutable ring carbon of said fused ring formed by R^(x) andR^(y) is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

R¹ is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbonof Ring D is independently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

Z is a C₁₋₄ alkylidene chain;

L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R₆)CON(R⁶)—;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR_(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R^(2′) isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N—(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R₆)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)—, —C(R₆)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

Preferred rings formed by R^(x) and R^(y) include a 5-, 6-, or7-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.This provides a bicyclic ring system containing a pyrimidine ring.Examples of preferred pyrimidine ring systems of formula IIa are shownbelow.

More preferred pyrimidine ring systems of formula IIa include IIa-A,IIa-B, IIa-D, IIa-E, IIa-J, IIa-P, and IIa-V, most preferably IIa-A,IIa-B, IIa-D, IIa-E, and IIa-J.

The ring formed when R^(x) and R^(y) are taken together may besubstituted or unsubstituted. Suitable substituents include —R, halo,—O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR, —N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂,—N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R,—SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂,wherein R and R⁴ are as defined above. Preferred R^(x)/R^(y) ringsubstituents include —halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN,—O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂, —NR⁴COR, —NR⁴SO₂R,—SO₂N(R⁴)₂ wherein R is hydrogen or an optionally substituted C₁₋₆aliphatic group.

The R² and R^(2′) groups of formula IIa may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IIa compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IIainclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl or ethyl.

When the pyrazole ring system of formula IIa is monocyclic, preferred R²groups include hydrogen or a substituted or unsubstituted group selectedfrom aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples of suchpreferred R² groups include H, methyl, ethyl, propyl, cyclopropyl,i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R_(2′) group is hydrogen.

When Ring D of formula IIa is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IIa is bicyclic, preferred bicyclic Ring D groupsinclude naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IIa, preferred T—R⁵ or V—Z—R⁵ substituents include—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

Preferred formula IIa compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together with their intervening atoms toform a fused, unsaturated or partially unsaturated, 5-6 membered ringhaving 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

(b) R¹ is T-(Ring D), wherein T is a valence bond or a methylene unit;

(c) Ring D is a 5-7 membered monocyclic ring or an 8-10 memberedbicyclic ring selected from an aryl or heteroaryl ring;

(d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen; or R² and R^(2′) aretaken together to form an optionally substituted benzo ring; and

(e) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂.

More preferred compounds of formula IIa have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together to form a benzo, pyrido,cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;

(b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6membered monocyclic ring or an 8-10 membered bicyclic ring selected froman aryl or heteroaryl ring;

(c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

(d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—.

Even more preferred compounds of formula IIa have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together to form a benzo, pyrido,piperidino, or cyclohexo ring;

(b) R¹ is T-Ring D, wherein T is a valence bond and Ring D is a 5-6membered aryl or heteroaryl ring;

(c) R² is hydrogen or C₁₋₄ aliphatic and R^(2′) is hydrogen;

(d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl, and L is —O—, —S—, or —NH—; and

(e) Ring D is substituted by up to three substituents selected from—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R)COCH₂N(R)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring.

Representative compounds of formula IIa are shown below in Table 1.

TABLE 1

IIa-1

IIa-2

IIa-3

IIa-4

IIa-5

IIa-6

IIa-7

IIa-8

IIa-9

IIa-10

IIa-11

IIa-12

IIa-13

IIa-14

IIa-15

IIa-16

IIa-17

IIa-18

IIa-19

IIa-20

IIa-21

IIa-22

IIa-23

IIa-24

IIa-25

IIa-26

IIa-27

IIa-28

IIa-29

IIa-30

IIa-31

IIa-32

IIa-33

IIa-34

IIa-35

IIa-36

IIa-37

IIa-38

IIa-39

IIa-40

IIa-41

IIa-42

IIa-43

IIa-44

IIa-45

IIa-46

IIa-47

IIa-48

IIa-49

IIa-50

IIa-51

IIa-52

IIa-53

IIa-54

IIa-55

IIa-56

IIa-57

IIa-58

IIa-59

IIa-60

IIa-61

IIa-62

IIa-63

IIa-64

IIa-65

IIa-66

IIa-67

IIa-68

IIa-69

IIa-70

IIa-71

IIa-72

IIa-73

IIa-74

IIa-75

IIa-76

IIa-77

IIa-78

IIa-79

In another embodiment, this invention provides a composition comprisinga compound of formula IIa and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIa or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula IIa or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIa or apharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIa or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula IIa or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a CDK-2-mediated disease with a CDK-2 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIa or apharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting CDK-2 activity ina patient, which method comprises administering to the patient acompound of formula IIa or a composition comprising said compound.

Another aspect of this invention relates to a method of treating orpreventing a Src-mediated disease with a Src inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIa or apharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting Src activity in apatient, which method comprises administering to the patient a compoundof formula IIa or a composition comprising said compound.

Another method relates to inhibiting Aurora-2, GSK-3, CDK2, or Srcactivity in a biological sample, which method comprises contacting thebiological sample with the Aurora-2, GSK-3, CDK2, or Src inhibitor offormula IIa, or a pharmaceutical composition thereof, in an amounteffective to inhibit Aurora-2, GSK-3, CDK2, or Src.

Each of the aforementioned methods directed to the inhibition ofAurora-2, GSK-3, CDK2, or Src, or the treatment of a disease alleviatedthereby, is preferably carried out with a preferred compound of formulaIIa, as described above.

Another embodiment of this invention relates to compounds of formulaIIb:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein;

R^(x) and R^(y) are taken together with their intervening atoms to forma fused, unsaturated or partially unsaturated, 5-7 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereineach substitutable ring carbon of said fused ring formed by R^(x) andR^(y) is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

R¹ is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbonof Ring D is independently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

Z is a C₁₋₄ alkylidene chain;

L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R^(2′) isindependently substituted by halo, oxo, —ON, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

Preferred rings formed by R^(x) and R^(y) include a 5-, 6-, or7-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.This provides a bicyclic ring system containing a pyrimidine ring.Examples of preferred pyrimidine ring systems of formula IIb are shownbelow.

More preferred pyrimidine ring systems of formula IIb include IIb-A,IIb-B, IIb-D, IIb-E, IIb-J, IIb-P, and IIb-V, most preferably IIb-A,IIb-B, IIb-D, IIb-E, and IIb-J.

The ring formed when R^(x) and R^(y) are taken together may besubstituted or unsubstituted. Suitable substituents include —R, halo,—O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR, —N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂,—N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R,—SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁶)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R ⁴)₂, —N(R⁴SO₂N(R⁴, —N(R⁴)SO₂R, or —OC(═O)N(R)₂, Rand R⁴ are as defined above. Preferred R^(x)/R^(y) ring substituentsinclude —halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂,—O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂, —NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R ishydrogen or an optionally substituted C₁₋₆ aliphatic group.

The R² and R^(2′) groups of formula IIb may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IIb compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IIbinclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl or ethyl.

When the pyrazole ring system of formula IIb is monocyclic, preferred R²groups include hydrogen or a substituted or unsubstituted group selectedfrom aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples of suchpreferred R² groups include H, methyl, ethyl, propyl, , cyclopropyl,i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

When Ring D of formula IIb is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IIb is bicyclic, preferred bicyclic Ring D groupsinclude naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IIb, preferred T—R⁵ or V—Z—R⁵ substituents include—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

Preferred formula IIb compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together with their intervening atoms toform a fused, unsaturated or partially unsaturated, 5-6 membered ringhaving 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

(b) R¹ is T-(Ring D), wherein T is a valence bond or a methylene unit;

(c) Ring D is a 5-7 membered monocyclic ring or an 8-10 memberedbicyclic ring selected from an aryl or heteroaryl ring;

(d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen; or R² and R^(2′) aretaken together to form an optionally substituted benzo ring; and

(e) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂.

More preferred compounds of formula IIb have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together to form a benzo, pyrido,cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;

(b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6membered monocyclic ring or an 8-10 membered bicyclic ring selected froman aryl or heteroaryl ring;

(c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

(d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—.

Even more preferred compounds of formula IIb have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together to form a benzo, pyrido,piperidino, or cyclohexo ring;

(b) R¹ is T-Ring D, wherein T is a valence bond and Ring D is a 5-6membered aryl or heteroaryl ring;

(c) R² is hydrogen or C₁₋₄ aliphatic and R^(2′) is hydrogen;

(d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl, and L is —O—, —S—, or —NH—; and

(e) Ring D is substituted by up to three substituents selected from—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring.

Representative compounds of formula IIb are shown below in Table 2.

TABLE 2

IIb-1

IIb-2

IIb-3

IIb-4

IIb-5

IIb-6

IIb-7

IIb-8

IIb-9

In another embodiment, this invention provides a composition comprisinga compound of formula IIb and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIb or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula IIb or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIb or apharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIb or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula IIb or a composition comprising saidcompound.

Another method relates to inhibiting Aurora-2 or GSK-3 activity in abiological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IIb, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IIb, asdescribed above.

Another embodiment of this invention relates to compounds of formulaIIc:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein;

R^(x) and R^(y) are taken together with their intervening atoms to forma fused, unsaturated or partially unsaturated, 5-7 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereineach substitutable ring carbon of said fused ring formed by R^(x) andR^(y) is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

R¹ is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbonof Ring D is independently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

Z is a C₁₋₄ alkylidene chain;

L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R^(2′) isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—, —CO₂—,—N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—,—C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—,—C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—,—C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

Preferred rings formed by R^(x) and R^(y) include a 5-, 6-, or7-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.This provides a bicyclic ring system containing a pyrimidine ring.Examples of preferred pyrimidine ring systems of formula IIc are shownbelow.

More preferred pyrimidine ring systems of formula IIc include IIc-A,IIc-B, IIc-D, IIc-E, IIc-J, IIc-P, and IIc-V, most preferably IIc-A,IIC-B, IIc-D, IIC-E, and IIc-J.

The ring formed when R^(x) and R^(y) of formula IIc are taken togethermay be substituted or unsubstituted. Suitable substituents include —R,halo, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR, —N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂,—N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R,—SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂,R and R⁴ are as defined above. Preferred R^(x)/R^(y) ring substituentsinclude —halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂,—O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂, —NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R ishydrogen or an optionally substituted C₁₋₆ aliphatic group.

The R² and R^(2′) groups of formula IIc may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IIc compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IIcinclude one or more of the following: is —halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

When the pyrazole ring system of formula IIc is monocyclic, preferred R²groups include hydrogen or a substituted or unsubstituted group selectedfrom aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples of suchpreferred R² groups include H, methyl, ethyl, propyl, , cyclopropyl,i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

When Ring D of formula IIc is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IIc is bicyclic, preferred bicyclic Ring D groupsinclude naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IIc, preferred T—R⁵ or V—Z—R⁵ substituents include—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(Cl₄ aliphatic) suchas —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic) suchas —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl, isopropyl,or t-butyl, and CO₂(C₁₋₄, aliphatic).

Preferred formula IIc compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together with their intervening-atoms toform a fused, unsaturated or partially unsaturated, 5-6 membered ringhaving 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

(b) R¹ is T-(Ring D), wherein T is a valence bond or a methylene unit;

(c) Ring D is a 5-7 membered monocyclic ring or an 8-10 memberedbicyclic ring selected from an aryl or heteroaryl ring;

(d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen; or R² and R^(2′) aretaken together to form an optionally substituted benzo ring; and

(e)—R³ is selected from —R, —halo, —OR, or —N(R⁴)₂.

More preferred compounds of formula IIc have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together to form a benzo, pyrido,cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;

(b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6membered monocyclic ring or an 8-10 membered bicyclic ring selected froman aryl or heteroaryl ring;

(c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

(d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—.

Even more preferred compounds of formula IIc have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together to form a benzo, pyrido,piperidino, or cyclohexo ring;

(b) R¹ is T-Ring D, wherein T is a valence bond and Ring D is a 5-6membered aryl or heteroaryl ring;

(c) R² is hydrogen or C₁₋₄ aliphatic and R^(2′) is hydrogen;

(d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl, and L is —O—, —S—, or —NH—; and

(e) Ring D is substituted by up to three substituents selected from—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring.

Preferred compounds of formula IIc include compounds of formula IIc:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein;

R^(x) and R^(y) are taken together with their intervening atoms to forma fused benzo ring, wherein each substitutable ring carbon of said fusedring formed by R^(x) and R^(y) is independently substituted by T—R³, orL—Z—R³;

R¹ is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbonof Ring D is independently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

Z is a C₁₋₄ alkylidene chain;

L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R^(2′) isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)—OC(═O)R,—N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N((R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶))N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

The ring formed when R^(x) and R^(y) of formula IIc′ are taken togethermay be substituted or unsubstituted. Suitable substituents include —R,halo, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR, —N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂,—N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R,—SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂,wherein R and R⁴ are as defined above. Preferred R^(x)/R^(y) ringsubstituents include —halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN,—O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂, —NR⁴COR, —NR⁴SO₂R,—SO₂N(R⁴)₂, wherein R is hydrogen or an optionally substituted C₁₋₆aliphatic group.

The R² and R^(2′) groups of formula IIc′ may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IIc′ compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IIc′include one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

When the pyrazole ring system of formula IIc′ is monocyclic, preferredR² groups include hydrogen or a substituted or unsubstituted groupselected from aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples ofsuch preferred R² groups include H, methyl, ethyl, propyl, cyclopropyl,i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

When Ring D of formula IIc′ is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IIc′ is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IIc′, preferred T—R⁵ or V—Z—R⁵ substituents include—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

Preferred formula IIc′ compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) R¹ is T-(Ring D), wherein T is a valence bond or a methylene unit;

(b) Ring D is a 5-7 membered monocyclic ring or an 8-10 memberedbicyclic ring selected from an aryl or heteroaryl ring;

(c) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen; or R² and R^(2′) aretaken together to form an optionally substituted benzo ring; and

(d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂.

More preferred compounds of formula IIc′ have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6membered monocyclic ring or an 8-10 membered bicyclic ring selected froman aryl or heteroaryl ring;

(b) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

(c) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—.

Even more preferred compounds of formula IIc′ have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R¹ is T-Ring D, wherein T is a valence bond and Ring D is a 5-6membered aryl or heteroaryl ring;

(b) R² is hydrogen or C₁₋₄ aliphatic and R^(2′) is hydrogen;

(c) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl, and L is —O—, —S—, or —NH—; and

(d) Ring D is substituted by up to three substituents selected from—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring.

Other preferred compounds of formula IIc include compounds of formulaIIc″:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein;

R^(x) and R^(y) are taken together with their intervening atoms to forma fused, unsaturated or partially unsaturated, 5-7 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereineach substitutable ring carbon of said fused ring formed by R^(x) andR^(y) is optionally substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isoptionally substituted by R⁴; provided that said fused ring formed byR^(x) and R^(y) is other than benzo;

R¹ is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbonof Ring D is independently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

Z is a C₁₋₄ alkylidene chain;

L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)_(N(R) ⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶ )SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R^(2′) isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁶)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

Preferred rings formed by R^(x) and R^(y) of formula IIc″ include a 5-,6-, or 7-membered unsaturated or partially unsaturated ring having 1-2heteroatoms, or a partially unsaturated carbocyclo ring, wherein saidR^(x)/R^(y) ring is optionally substituted. This provides a bicyclicring system containing a pyrimidine ring. Examples of preferredpyrimidine ring systems of formula IIc″ are shown below.

More preferred pyrimidine ring systems of formula IIc″ include IIc″-B,IIC-D, IIc-E, IIC-J, IIc-P, and IIc-V, most preferably IIC-B, IIC-D,IIC-E, and IIc-J.

The ring formed when R^(x) and R^(y) of formula IIc″ are taken togethermay be substituted or unsubstituted. Suitable substituents include —R,halo, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR, —N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂,—N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R,—SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂,wherein R and R⁴ are as defined above. Preferred R^(x)/R^(y) ringsubstituents include —halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN,—O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂, —NR⁴COR, —NR⁴SO₂R,—SO₂N(R⁴)₂ wherein R is hydrogen or an optionally substituted C₁₋₆aliphatic group.

The R² and R^(2″) groups of formula IIc″ may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IIc″ compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IIc″include one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

When the pyrazole ring system of formula IIc″ is monocyclic, preferredR² groups include hydrogen or a substituted or unsubstituted groupselected from aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples ofsuch preferred R² groups include H, methyl, ethyl, propyl, cyclopropyl,i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

When Ring D of formula IIc″ is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IIc″ is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IIc″, preferred T—R⁵ or V—Z—R⁵ substituents include—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂—(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

Preferred formula IIc″ compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together with their intervening atoms toform a fused, unsaturated or partially unsaturated, 5-6 membered ringhaving 1-2 heteroatoms selected from oxygen, sulfur, or nitrogen, or apartially unsaturated 6-membered carbocyclo ring, wherein eachsubstitutable ring carbon of said fused ring formed by R^(x) and R^(y)is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

(b) R¹ is T-(Ring D), wherein T is a valence bond or a methylene unit,and Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclicaryl or heteroaryl ring;

(c) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen; or R² and R^(2′) aretaken together to form an optionally substituted benzo ring; and

(d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂.

More preferred compounds of formula IIc″ have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together to form a benzo, pyrido,cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

(b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6membered monocyclic ring or an 8-10 membered bicyclic ring selected froman aryl or heteroaryl ring;

(c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

(d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R)—.

Even more preferred compounds of formula IIc″ have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together to form a pyrido, piperidino, orcyclohexo ring, wherein each substitutable ring carbon of said fusedring formed by R^(x) and R^(y) is independently substituted by oxo,T—R³, or L—Z—R³, and each substitutable ring nitrogen of said ringformed by R^(x) and R^(y) is independently substituted by R⁴;

(b) R¹ is T-Ring D, wherein T is a valence bond and Ring D is a 5-6membered aryl or heteroaryl ring;

(c) R² is hydrogen or C₁₋₄ aliphatic and R^(2′) is hydrogen;

(d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl, and L is —O—, —S—, or —NH—; and

(e) Ring D is substituted by up to three substituents selected from—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂ wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring.

Representative compounds of formula IIc are shown below in Table 3.

TABLE 3

IIc-1

IIc-2

IIc-3

IIc-4

IIc-5

IIc-6

IIc-7

IIc-8

IIc-9

IIc-10

IIc-11

IIc-12

IIc-13

IIc-14

IIc-15

IIc-16

IIc-17

IIc-18

IIc-19

IIc-20

IIc-21

IIc-22

IIc-23

IIc-24

IIc-25

IIc-26

IIc-27

IIc-28

IIc-29

IIc-30

IIc-31

IIc-32

IIc-33

IIc-34

IIc-35

IIc-36

IIc-37

IIc-38

IIc-39

IIc-40

IIc-41

IIc-42

IIc-43

IIc-44

IIc-45

IIc-46

IIc-47

IIc-48

IIc-49

IIc-50

IIc-51

IIc-52

IIc-53

IIc-54

IIc-55

IIc-56

IIc-57

IIc-58

IIc-59

IIc-60

IIc-61

IIc-62

IIc-63

IIc-64

IIc-65

IIc-66

IIc-67

IIc-68

IIc-69

IIc-70

IIc-71

IIc-72

IIc-73

IIc-74

IIc-75

IIc-76

IIc-77

IIc-78

IIc-79

IIc-80

IIc-81

IIc-82

IIc-83

IIc-84

IIc-85

IIc-86

IIc-87

IIc-88

IIc-89

IIc-90

In another embodiment, this invention provides a composition comprisinga compound of formula IIc, IIc′, or IIc″, and a pharmaceuticallyacceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIc, IIc′, or IIc″, or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula IIc, IIc′, or IIc″, or a compositioncomprising said compound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIc, IIc′, orIIc″, or a pharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIc, IIc′, orIIc″, or a pharmaceutical composition thereof. This method is especiallyuseful for diabetic patients. Another method relates to inhibiting theproduction of hyperphosphorylated Tau protein, which is useful inhalting or slowing the progression of Alzheimer's disease. Anothermethod relates to inhibiting the phosphorylation of β-catenin, which isuseful for treating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula IIc, IIc′, or IIc″, or a compositioncomprising said compound.

Another aspect of this invention relates to a method of treating orpreventing a Src-mediated disease with a Src inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIc, IIc′, orIIc″, or a pharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting Src activity in apatient, which method comprises administering to the patient a compoundof formula IIc, IIc′, or IIc″, or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing an ERK-2-mediated diseases with an ERK-2 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IIc, IIc′,or IIc″, or a pharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting ERK-2 activity ina patient, which method comprises administering to the patient acompound of formula IIc, IIc′, or IIc″, or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing an AKT-mediated diseases with an AKT inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIc, IIc′, orIIc″, or a pharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting AKT activity in apatient, which method comprises administering to the patient a compoundof formula IIc, IIc′, or IIc″, or a composition comprising saidcompound.

Another method relates to inhibiting Aurora-2, GSK-3, Src, ERK-2, or AKTactivity in a biological sample, which method comprises contacting thebiological sample with the Aurora-2, GSK-3, Src, ERK-2, or AKT inhibitorof formula IIc, IIc′, or IIc″, or a pharmaceutical composition thereof,in an amount effective to inhibit Aurora-2, GSK-3, Src, ERK-2, or AKT.

Each of the aforementioned methods directed to the inhibition ofAurora-2, GSK-3, Src, ERK-2, or AKT, or the treatment of a diseasealleviated thereby, is preferably carried out with a preferred compoundof formula IIc, IIc′, or IIc″, as described above.

Another embodiment that is particularly useful for treatingAurora-2-mediated diseases relates to compounds of formula IId:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein;

Q′ is selected from —C(R^(6′))₂—, 1,2-cyclopropanediyl,1,2-cyclobutanediyl, or 1,3-cyclobutanediyl;

R^(x) and R^(y) are taken together with their intervening atoms to forma fused, unsaturated or partially unsaturated, 5-7 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereineach substitutable ring carbon of said fused ring formed by R^(x) andR^(y) is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R₄;

R¹ is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbonof Ring D is independently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q′ is—C(R^(6′))₂— a methylene group of said C₁₋₄ alkylidene chain isoptionally replaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—, —SO₂—,—SO₂NH—, —NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;

Z is a C₁₋₄ alkylidene chain;

L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R^(2′) isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)—₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —So₂R⁷;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R^(6′) is independently selected from hydrogen or a C₁₋₄ aliphaticgroup, or two R^(6′) on the same carbon atom are taken together to forma 3-6 membered carbocyclic ring; and

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

Preferred rings formed by R^(x) and R^(y) include a 5-, 6-, or7-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.This provides a bicyclic ring system containing a pyrimidine ring.Examples of preferred pyrimidine ring systems of formula IId are shownbelow.

More preferred pyrimidine ring systems of formula IId include IId-A,IId-B, IId-D, IId-E, IId-J, lId-P, and IId-V, most preferably IId-A,IId-B, IId-D, IId-E, and IId-J.

The ring formed when R^(x) and R^(y) of formula IId are taken togethermay be substituted or unsubstituted. Suitable substituents include —R,halo, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR, —N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂,—N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R,—SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂,R and R⁴ are as defined above. Preferred R^(x)/R^(y) ring substituentsinclude —halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂,—O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂, —NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R ishydrogen or an optionally substituted C₁₋₆ aliphatic group.

The R² and R^(2′) groups of formula lid may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IId compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IIdinclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

When the pyrazole ring system of formula IId is monocyclic, preferred R²groups include hydrogen or a substituted or unsubstituted group selectedfrom aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples of suchpreferred R² groups include H, methyl, ethyl, propyl, cyclopropyl,i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

When Ring D of formula IId is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula lId is bicyclic, preferred bicyclic Ring D groupsinclude naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IId, preferred T—R⁵ or V—Z—R⁵ substituents include—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

Preferred Q′ groups of formula lId include —C(R^(6′))₂— or1,2-cyclopropanediyl, wherein each R^(6′) is independently selected fromhydrogen or methyl. A more preferred Q′ group is —CH₂—.

Preferred formula IIc compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together with their intervening atoms toform a fused, unsaturated or partially unsaturated, 5-6 membered ringhaving 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

(b) R¹ is T-(Ring D), wherein T is a valence bond or a methylene unitand wherein said methylene unit is optionally replaced by —O—, —NH—, or—S—;

(c) Ring D is a 5-7 membered monocyclic ring or an 8-10 memberedbicyclic ring selected from an aryl or heteroaryl ring;

(d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen; or R² and R_(2′) aretaken together to form an optionally substituted benzo ring; and

(e) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂.

More preferred compounds of formula IIc have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together to form a benzo, pyrido,cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;

(b) R¹ is T-(Ring D), wherein T is a valence bond or a methylene unitand wherein said methylene unit is optionally replaced by —O—, and RingD is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ringselected from an aryl or heteroaryl ring;

(c) R² is —R and R_(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring;

(d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—; and

(e) Q′ is —C(R⁶)₂— or 1,2-cyclopropanediyl, wherein each R^(6′) isindependently selected from hydrogen or methyl.

Even more preferred compounds of formula IIc have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together to form a benzo, pyrido,piperidino, or cyclohexo ring;

(b) R¹ is T-Ring D, wherein T is a valence bond and Ring D is a 5-6membered aryl or heteroaryl ring;

(c) R² is hydrogen or C₁₋₄ aliphatic and R^(2′) is hydrogen;

(d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl-, phenyl, or 5-6membered heteroaryl, and L is —O—, —S—, or —NH—;

(e) Ring D is substituted by up to three substituents selected from—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring; and

(f) Q′ is —CH₂—.

Representative compounds of formula IId are shown below in Table 4.

TABLE 4

IId-1

IId-2

IId-3

IId-4

IId-5

IId-6

IId-7

IId-8

IId-9

IId-10

IId-11

IId-12

IId-13

IId-14

IId-15

IId-16

IId-17

IId-18

IId-19

In another embodiment, this invention provides a composition comprisinga compound of formula IId and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIId or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula IId or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IId or apharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IId or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula IId or a composition comprising saidcompound.

Another method relates to inhibiting Aurora-2 or GSK-3 activity in abiological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IId, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IId, asdescribed above.

Another embodiment of this invention relates to compounds of formulaIIIa:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

R^(x) and R^(y) are independently selected from T—R³ or L—Z—R³;

R¹ is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbonof Ring D is independently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

Z is a C₁₋₄ alkylidene chain;

L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R^(2′) isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an 10 optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

each R⁷ is independently selected from hydrogen or an is optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

Preferred R^(x) groups of formula IIIa include hydrogen, alkyl- ordialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

Preferred R^(y) groups of formula IIIa include T—R³ or L—Z—R³ wherein Tis a valence bond or a methylene, L is —O—, —S—, or —N(R⁴)—, —C(R⁶)₂O—,—CO— and R³ is —R, —N(R⁴)₂, or —OR. Examples of preferred R^(y) groupsinclude 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl,alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such asmethoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylaminoor dimethylamino, alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy, acetamido, optionally substituted phenyl such asphenyl or halo-substituted phenyl.

The R² and R^(2′) groups of formula IIIa may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IIIa compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IIIainclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C⁴ alkyl), —CN, —SO₂(C₁₋₄ alkyl),—SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —C(O)NH₂,and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight, branched,or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group is methyl.

When the pyrazole ring system of formula IIIa is monocyclic, preferredR²groups include hydrogen or a substituted or unsubstituted groupselected from aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples ofsuch preferred R² groups include H, methyl, ethyl, propyl, ,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

When Ring D of formula IIa is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IIIa is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IIIa, preferred T—R⁵ or V—Z—R⁵ substituents include—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

Preferred formula IIIa compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄aliphatic group;

(b) R^(y) is T—R³ or L—Z—R³, wherein T is a valence bond or a methyleneand R³ is —R, —N(R⁴)₂, or —OR;

(c) R¹ is T-(Ring D), wherein T is a valence bond or a methylene unit;

(d) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclicaryl or heteroaryl ring; and

(e) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′) aretaken together to form an optionally substituted benzo ring.

More preferred compounds of formula IIIa have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(y) is T—R³ or L—Z—R³ wherein T is a valence bond or a methyleneand R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl;

(b) R¹ is T-(Ring D), wherein T is a valence bond;

(c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclicaryl or heteroaryl ring;

(d) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

(e) L is —O—, —S—, or —N(R⁴)—.

Even more preferred compounds of formula IIIa have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl,methylamino or acetimido;

(b) R^(y) is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- ordialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionallysubstituted phenyl, or methoxymethyl;

(c) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6membered aryl or heteroaryl ring, wherein Ring D is optionallysubstituted with one to two groups selected from —halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂; and

(d) R² is hydrogen or a substituted or unsubstituted C₁₋₆ aliphatic, andL is —O—, —S—, or —NH—.

Representative compounds of formula IIIa are shown below in Table 5.

TABLE 5

IIIa-1

IIIa-2

IIIa-3

IIIa-4

IIIa-5

IIIa-6

IIIa-7

IIIa-8

IIIa-9

IIIa-10

IIIa-11

IIIa-12

IIIa-13

IIIa-14

IIIa-15

IIIa-16

IIIa-17

IIIa-18

IIIa-19

IIIa-20

IIIa-21

IIIa-22

IIIa-23

IIIa-24

IIIa-25

IIIa-26

IIIa-27

IIIa-28

IIIa-29

IIIa-30

IIIa-31

IIIa-32

IIIa-33

IIIa-34

IIIa-35

IIIa-36

IIIa-37

IIIa-38

IIIa-39

IIIa-40

IIIa-41

IIIa-42

IIIa-43

IIIa-44

IIIa-45

IIIa-46

IIIa-47

IIIa-48

IIIa-49

IIIa-50

IIIa-51

IIIa-52

IIIa-53

IIIa-54

IIIa-55

IIIa-56

IIIa-57

IIIa-58

IIIa-59

IIIa-60

IIIa-61

IIIa-62

IIIa-63

In another embodiment, this invention provides a composition comprisinga compound of formula IIIa and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIIa or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula IIIa or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIIa or apharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIIa or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula IIIa or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a Src-mediated disease with a Src inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIIa or apharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting Src activity in apatient, which method comprises administering to the patient a compoundof formula IIIa or a composition comprising said compound.

Another method relates to inhibiting Aurora-2, GSK-3, or Src activity ina biological sample, which method comprises contacting the biologicalsample with the Aurora-2, GSK-3, or Src inhibitor of formula IIIa, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2, GSK-3, or Src.

Each of the aforementioned methods directed to the inhibition ofAurora-2, GSK-3, or Src, or the treatment of a disease alleviatedthereby, is preferably carried out with a preferred compound of formulaIIIa, as described above.

Another embodiment of this invention relates to compounds of formulaIIIb:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

R^(x) and R^(y) are independently selected from T—R³ or L—Z—R³;

R¹ is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbonof Ring D is independently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

Z is a C₁₋₄ alkylidene chain;

L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R^(2′) isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

Preferred R^(x) groups of formula IIIb include hydrogen, alkyl- ordialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

Preferred R^(y) groups of formula IIIb include T—R³ or L—Z—R³ wherein Tis a valence bond or a methylene, L is —O—, —S—, or —N(R⁴)—, —C(R⁶)₂O—,—CO— and R³ is —R, —N(R⁴)₂, or —OR. Examples of preferred R^(y) groupsinclude 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl,alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such asmethoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylaminoor dimethylamino, alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy, acetamido, optionally substituted phenyl such asphenyl or halo-substituted phenyl.

The R² and R^(2′) groups of formula IIIb may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IIIb compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IIIbinclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

When the pyrazole ring system of formula IIIb is monocyclic, preferredR² groups include hydrogen or a substituted or unsubstituted groupselected from aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples ofsuch preferred R² groups include H, methyl, ethyl, propyl, cyclopropyl,i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

When Ring D of formula IIIb is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IIIb is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IIIb, preferred T—R⁵ or V—Z—R⁵ substituents include—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCHCH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHS₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t—Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

Preferred formula IIIb compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄aliphatic group;

(b) R^(y) is T—R³ or L—Z—R³, wherein T is a valence bond or a methyleneand R³ is —R, —N(R⁴)₂, or —OR;

(c) R¹ is T-(Ring D), wherein T is a valence bond or a methylene unit;

(d) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclicaryl or heteroaryl ring; and

(e) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′) aretaken together to form an optionally substituted benzo ring.

More preferred compounds of formula IIIb have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(y) is T—R³ or L—Z—R³ wherein T is a valence bond or a methyleneand R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl;

(b) R¹ is T-(Ring D), wherein T is a valence bond;

(c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclicaryl or heteroaryl ring;

(d) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, c₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

(e) L is —O—, —S—, or —N(R⁴)—.

Even more preferred compounds of formula IIIb have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl,methylamino or acetimido;

(b) R^(y) is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- ordialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionallysubstituted phenyl, or methoxymethyl;

(c) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6membered aryl or heteroaryl ring, wherein Ring D is optionallysubstituted with one to two groups selected from —halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂; and

(d) R² is hydrogen or a substituted or unsubstituted C₁₋₆ aliphatic, andL is —O—, —S—, or —NH—.

Representative compounds of formula IIIb are shown below in Table 6.

TABLE 6

IIIb-1

IIIb-2

IIIb-3

IIIb-4

IIIb-5

IIIb-6

IIIb-7

IIIb-8

IIIb-9

IIIb-10

IIIb-11

IIIb-12

IIIb-13

IIIb-14

IIIb-15

IIIb-16

IIIb-17

IIIb-18

IIIb-19

IIIb-20

IIIb-21

IIIb-22

IIIb-23

IIIb-24

IIIb-25

IIIb-26

IIIb-27

IIIb-28

IIIb-29

IIIb-30

In another embodiment, this invention provides a composition comprisinga compound of formula IIIb and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIIb or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula IIIb or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIIb or apharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIIb or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula IIIb or a composition comprising saidcompound.

Another method relates to inhibiting Aurora-2 or GSK-3 activity in abiological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IIIb, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IIIb, asdescribed above.

Another embodiment of this invention relates to compounds of formulaIIIc:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

R^(x) and R^(y) are independently selected from T—R³ or L—Z—R³;

R¹ is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbonof Ring D is independently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

Z is a C₁₋₄ alkylidene chain;

L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R^(2′) isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

Preferred R^(x) groups of formula IIIc include hydrogen, alkyl- ordialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

Preferred R^(y) groups of formula IIIc include T—R³ or L—Z—R³ wherein Tis a valence bond or a methylene, L is —O—, —S—, or —N(R⁴)—, —C(R⁶)₂O—,—CO— and R³ is —R, —N(R⁴)₂, or —OR. Examples of preferred R^(y) groupsinclude 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl,alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such asmethoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylaminoor dimethylamino, alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy, acetamido, optionally substituted phenyl such asphenyl or halo-substituted phenyl.

The R² and R^(2′) groups of formula IIIc may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IIIc compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IIIcinclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

When the pyrazole ring system of formula IIIc is monocyclic, preferredR² groups include hydrogen or a substituted or unsubstituted groupselected from aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples ofsuch preferred R² groups include H, methyl, ethyl, propyl, cyclopropyl,i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

When Ring D of formula IIIc is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IIIc is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IIIc, preferred T—R⁵ or V—Z—R⁵ substituents include—halo, —CN, —NO₂, —N(R )₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF³, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t—Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

Preferred formula IIIc compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄aliphatic group;

(b) R^(y) is T—R³ or L—Z—R³, wherein T is a valence bond or a methyleneand R³ is —R, —N(R⁴)₂, or —OR;

(c) R¹ is T-(Ring D), wherein T is a valence bond or a methylene unit;

(d) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclicaryl or heteroaryl ring; and

(e) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′) aretaken together to form an optionally substituted benzo ring.

More preferred compounds of formula IIIc have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(y) is T—R³ or L—Z—R³ wherein T is a valence bond or a methyleneand R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromC₁₋₆ aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 memberedheteroaryl;

(b) R¹ is T-(Ring D), wherein T is a valence bond;

(c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclicaryl or heteroaryl ring;

(d) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

(e) L is —O—, —S—, or —N(R⁴)—.

Even more preferred compounds of formula IIIc have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl,methylamino or acetimido;

(b) R^(y) is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- ordialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionallysubstituted phenyl, or methoxymethyl;

(c) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6membered aryl or heteroaryl ring, wherein Ring D is optionallysubstituted with one to two groups selected from —halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂; and

(d) R² is hydrogen or a substituted or unsubstituted C₁₋₆ aliphatic, andL is —O—, —S—, or —NH—.

Representative compounds of formula IIIc are shown below in Table 7.

TABLE 7

IIIc-1

IIIc-2

IIIc-3

IIIc-4

IIIc-5

IIIc-6

IIIc-7

IIIc-8

IIIc-9

IIIc-10

IIIc-11

IIIc-12

IIIc-13

IIIc-14

IIIc-15

IIIc-16

IIIc-17

IIIc-18

IIIc-19

IIIc-20

IIIc-21

IIIc-22

IIIc-23

IIIc-24

IIIc-25

IIIc-26

In another embodiment, this invention provides a composition comprisinga compound of formula IIIc and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIc or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula IIIc or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIIc or apharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIIc or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula IIIc or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a Src-mediated disease with a Src inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIIc or apharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting Src activity in apatient, which method comprises administering to the patient a compoundof formula IIIc or a composition comprising said compound.

Another method relates to inhibiting Aurora-2, GSK-3, or Src activity ina biological sample, which method comprises contacting the biologicalsample with the Aurora-2, GSK-3, or Src inhibitor of formula IIIc, or apharmaceutical composition thereof, in an amount effective to Aurora-2,GSK-3, or Src.

Each of the aforementioned methods directed to the inhibition ofAurora-2, GSK-3, or Src, or the treatment of a disease alleviatedthereby, is preferably carried out with a preferred compound of formulaIIIc, as described above.

Another embodiment of this invention relates to compounds of formulaIIId:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Q′ is selected from —C(R^(6′))₂—, 1,2-cyclopropanediyl,1,2-cyclobutanediyl, or 1,3-cyclobutanediyl;

R^(x) and R^(y) are independently selected from T—R³ or L—Z—R³;

R¹ is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each, substitutable ring carbonof Ring D is independently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q′ is—C(R^(6′))₂— a methylene group of said C₁₋₄ alkylidene chain isoptionally replaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—, —SO₂—,—SO₂NH—, —NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;

Z is a C₁₋₄alkylidene chain;

L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R^(2′) isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R₄)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—,—C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R^(6′) is independently selected from hydrogen or a C₁₋₄ aliphaticgroup, or two R^(6′) on the same carbon atom are taken together to forma 3-6 membered carbocyclic ring; and

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

Preferred R^(x) groups of formula IIId include hydrogen, alkyl- ordialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

Preferred R^(y) groups of formula IIId include T—R³ or L—Z—R³ wherein Tis a valence bond or a methylene, L is —O—, —S—, or —N(R⁴)—, —C(R⁶)₂O—,—CO— and R³ is —R, —N(R⁴)₂, or —OR. Examples of preferred R^(y) groupsinclude 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl,alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such asmethoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylaminoor dimethylamino, alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy, acetamido, optionally substituted phenyl such asphenyl or halo-substituted phenyl.

The R² and R^(2′) groups of formula IIId may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IId compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IIIdinclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

When the pyrazole ring system of formula IIId is monocyclic, preferredR² groups include hydrogen or a substituted or unsubstituted groupselected from aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples ofsuch preferred R² groups include H, methyl, ethyl, propyl, cyclopropyl,i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

When Ring D of formula IIId is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IIId is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IIId, preferred T—R⁵ or V—Z—R⁵ substituents include—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t—Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

Preferred Q′ groups of formula IIId include —C(R⁶)₂— or1,2-cyclopropanediyl, wherein each R⁶ is independently selected fromhydrogen or methyl. A more preferred Q′ group is —CH₂—.

Preferred formula IIId compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄aliphatic group;

(b) R^(y) is T—R³ or L—Z—R³, wherein T is a valence bond or a methyleneand R³ is —R, —N(R⁴)₂, or —OR;

(c) R¹ is T-(Ring D), wherein T is a valence bond or a methylene unitand wherein said methylene unit is optionally replaced by —O—, —NH—, or—S—;

(d) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclicaryl or heteroaryl ring; and

(e) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′) aretaken together to form an optionally substituted benzo ring.

More preferred compounds of formula IIId have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(y) is T—R³ or L—Z—R³ wherein T is a valence bond or a methyleneand R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl;

(b) R¹ is T-(Ring D), wherein T is a valence bond;

(c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclicaryl or heteroaryl ring;

(d) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered is heterocyclic ring;

(e) L is —O—, —S—, or —N(R⁴)—; and

(f) Q′ is —C(R^(6′))₂— or 1,2-cyclopropanediyl, wherein each R^(6′) isindependently selected from hydrogen or methyl.

Even more preferred compounds of formula IIId have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl,methylamino or acetimido;

(b) R^(y) is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- ordialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionallysubstituted phenyl, or methoxymethyl;

(c) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6membered aryl or heteroaryl ring, wherein Ring D is optionallysubstituted with one to two groups selected from —halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂;

(d) R² is hydrogen or a substituted or unsubstituted C₁₋₆ aliphatic; andL is —O—, —S—, or —NH—; and

(e) Q′ is —CH₂—.

Representative compounds of formula IIId are shown below in Table 8.

TABLE 8

IIId-1

IIId-2

IIId-3

IIId-4

IIId-5

IIId-6

IIId-7

IIId-8

IIId-9

IIId-10

IIId-11

IIId-12

IIId-13

IIId-14

IIId-15

IIId-16

IIId-17

IIId-18

IIId-19

IIId-20

IIId-21

IIId-22

IIId-23

IIId-24

In another embodiment, this invention provides a composition comprisinga compound of formula IIId and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIId or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula IIId or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIId or apharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIId or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula IIId or a composition comprising saidcompound.

Another method relates to inhibiting Aurora-2 or GSK-3 activity in abiological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IIId, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IIId, asdescribed above.

Another embodiment of this invention relates to compounds of formulaIVa:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z¹ is nitrogen or C—R⁸ and Z² is nitrogen or CH, wherein one of Z¹ or Z²is nitrogen;

R^(x) and R^(y) are independently selected from T—R³ or L—Z—R³, or R^(x)and R^(y) are taken together with their intervening atoms to form afused, unsaturated or partially unsaturated, 5-7 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereineach substitutable ring carbon of said fused ring formed by R^(x) andR^(y) is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

R¹ is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbonof Ring D is independently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

Z is a C₁₋₄ alkylidene chain;

L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R)—;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R^(2′) isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂.

Preferred rings formed by R^(x) and R^(y) of formula IVa include a 5-,6-, or 7-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.This provides a bicyclic ring system containing a pyridine ring.Preferred pyridine ring systems of formula IVa are shown below.

More preferred pyridine ring systems of formula IVa include IVa-A,IVa-B, IVa-D, IVa-E, IVa-J, IVa-P, and IVa-V, most preferably IVa-A,IVa-B, IVa-D, IVa-E, and IVa-J. Even more preferred pyridine ringsystems of formula IVa are those described above, wherein Z′ is nitrogenand Z² is CH.

Preferred R^(x) groups of formula IVa include hydrogen, alkyl- ordialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

Preferred R^(y) groups of formula IVa include T—R³ or L—Z—R³ wherein Tis a valence bond or a methylene, L is —O—, —S—, or —N(R⁴)—, —C(R⁶)₂O—,—CO— and R³ is —R, —N(R⁴)₂, or —OR. Examples of preferred R^(y) groupsinclude 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl,alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such asmethoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylaminoor dimethylamino, alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy, acetamido, optionally substituted phenyl such asphenyl or halo-substituted phenyl.

The ring formed when the R^(x) and R^(y) groups of formula IVa are takentogether may be substituted or unsubstituted. Suitable substituentsinclude —R, halo, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR,—N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂, —N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂—CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, R and R⁴ are as defined above. PreferredR^(x)/R^(y) ring substituents include —halo, —R, —OR, —COR, —CO₂R,—CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂,—NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group.

The R² and R^(2′) groups of formula IVa may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IVa compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IVainclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄alkyl) group ismethyl.

When the pyrazole ring system of formula IVa is monocyclic, preferred R²groups include hydrogen or a substituted or unsubstituted group selectedfrom aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples of suchpreferred R² groups include H, methyl, ethyl, propyl, cyclopropyl,i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

When Ring D of formula IVa is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IVa is bicyclic, preferred bicyclic Ring D groupsinclude naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IVa, preferred T—R⁵ or V—Z—R⁵ substituents include—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAC, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t—Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic) suchas —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic) suchas —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl, isopropyl,or t-butyl, and —CO₂(C₁₋₄ aliphatic).

Preferred R⁸ groups of formula IVa, when present, include R, OR, andN(R⁴)₂. Examples of preferred R⁸ include methyl, ethyl, NH₂,NH₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂O, (piperidin-1-yl)CH₂CH₂O,and NH₂CH₂CH₂O.

Preferred formula IVa compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄aliphatic group and R^(y) is T—R³ or L—Z—R³, wherein T is a valence bondor a methylene and R³ is —R, —N(R⁴)₂, or —OR; or R^(x) and R^(y) aretaken together with their intervening atoms to form a fused, unsaturatedor partially unsaturated, 5-6 membered ring having 0-2 heteroatomsselected from oxygen, sulfur, or nitrogen, wherein each substitutablering carbon of said fused ring formed by R^(x) and R^(y) isindependently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

(b) R¹ is T-(Ring D), wherein T is a valence bond or a methylene unit;

(c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclicaryl or heteroaryl ring; and

(d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′) aretaken together to form an optionally substituted benzo ring.

More preferred compounds of formula IVa have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(y) is T—R³ or L—Z—R³ wherein T is a valence bond or a methyleneand R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R— is selected fromhydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl; or R^(x) and R^(y) are taken together with theirintervening atoms to form a benzo, pyrido, cyclopento, cyclohexo,cyclohepto, thieno, piperidino, or imidazo ring, wherein eachsubstitutable ring carbon of said fused ring formed by R^(x) and R^(y)is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

(b) R¹ is T-(Ring D), wherein T is a valence bond, and Ring D is a 5-6membered monocyclic or an 8-10 membered bicyclic aryl or heteroarylring;

(c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

(d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—.

Even more preferred compounds of formula IVa have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl,methylamino or acetamido and R^(y) is selected from 2-pyridyl,4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl,ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl,alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido,optionally substituted phenyl, or methoxymethyl; or R^(x) and are takentogether with their intervening atoms to form a benzo, pyrido,piperidino, or cyclohexo ring, wherein said ring is optionallysubstituted with —halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN,—O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —NO₂ —N(R⁴)₂, —NR⁴COR, —NR⁴SO₂R, or—SO₂N(R⁴)₂, wherein R is hydrogen or an optionally substituted C₁₋₆aliphatic group;

(b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6membered aryl or heteroaryl ring optionally substituted with one or twogroups selected from —halo, —CN, —NO₂, —N(R⁴)₂, optionally substitutedC₁₋₆ aliphatic, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R,—SO₂N(R⁴)₂, —N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂;

(c) R² is hydrogen or a substituted or unsubstituted group selected fromaryl, heteroaryl, or a C₁₋₆ aliphatic group, and R^(2′) is hydrogen; and

(d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl, and L—is —O—, —S—, or —NH—; and

(e) Ring D is substituted by up to three substituents selected from—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring.

Representative compounds of formula IVa are shown below in Table 9.

TABLE 9

IVa-1

IVa-2

IVa-3

IVa-4

IVa-5

IVa-6

IVa-7

IVa-8

IVa-9

IVa-10

IVa-11

IVa-12

In another embodiment, this invention provides a composition comprisinga compound of formula IVa and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIVa or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula IVa or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IVa or apharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IVa or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula IVa or a composition comprising saidcompound.

Another method relates to inhibiting Aurora-2 or GSK-3 activity in abiological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IVa, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IVa, asdescribed above.

Another embodiment of this invention relates to compounds of formulaIVb:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z¹ is nitrogen or C—R⁸ and Z² is nitrogen or CH, wherein one of Z¹ or Z²is nitrogen;

R^(x) and R^(y) are independently selected from T—R³ or L—Z—R³, or R^(x)and R^(y) are taken together with their intervening atoms to form afused, unsaturated or partially unsaturated, 5-7 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereineach substitutable ring carbon of said fused ring formed by R^(x) andR^(y) is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

R¹ is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbonof Ring D is independently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

Z is a C₁₋₄ alkylidene chain;

L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R^(2′) isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—, —CO₂—,—N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—,—C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—,—C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—,—C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R₇ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂.

Preferred rings formed by R^(x) and R^(y) of formula IVb include a 5-,6-, or 7-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.This provides a bicyclic ring system containing a pyrimidine is ring.Preferred pyrimidine ring systems of formula IVb are shown below.

More preferred pyrimidine ring systems of formula IVb include IVb-A,IVb-B, IVb-D, IVb-E, IVb-J, IVb-P, and IVb-V, most preferably IVb-A,IVb-B, IVb-D, IVb-E, and IVb-J. Even more preferred pyridine ringsystems of formula IVb are those described above, wherein Z¹ is nitrogenand Z² is CH.

Preferred R^(x) groups of formula IVb include hydrogen, alkyl- ordialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

Preferred R^(y) groups of formula IVb include T—R³ or L—Z—R³ wherein Tis a valence bond or a methylene, L is —O—, —S—, or —N(R⁴)—, —C(R⁶)₂O—,—CO— and R³ is —R, —N(R⁴)₂, or —OR. Examples of preferred R^(y) groupsinclude 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl,alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such asmethoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylaminoor dimethylamino, alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy, acetamido, optionally substituted phenyl such asphenyl or halo-substituted phenyl.

The ring formed when the R^(x) and R^(y) groups of formula Ivba aretaken together may be substituted or unsubstituted. Suitablesubstituents include —R, halo, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR,—N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂, —N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)_(2, —SO) ₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, R and R⁴ are as defined above. PreferredR^(x)/R^(y) ring substituents include —halo, —R, —OR, —COR, —CO₂R,—CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂,—NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group.

The R² and R^(2′) groups of formula IVb may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IVb compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IVbinclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

When the pyrazole ring system of formula IVb is monocyclic, preferred R²groups include hydrogen or a substituted or unsubstituted group selectedfrom aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples of suchpreferred R² groups include hydrogen, methyl, ethyl, propyl, ,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

When Ring D of formula IVb is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IVb is bicyclic, preferred bicyclic Ring D groupsinclude naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IVb, preferred T—R⁵ or V—Z—R⁵ substituents include—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAC, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t -Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

Preferred R⁸ groups of formula IVb, when present, include R, OR, andN(R⁴)₂. Examples of preferred R⁸ include methyl, ethyl, NH₂,NH₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂O, (piperidin-1-yl)CH₂CH₂O,and NH₂CH₂CH₂O.

Preferred formula IVb compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄aliphatic group and R^(y) is T—R³ or L—Z—R³, wherein T is a valence bondor a methylene and R³ is —R, —N(R⁴)₂, or —OR; or R^(x) and R^(y) aretaken together with their intervening atoms to form a fused, unsaturatedor partially unsaturated, 5-6 membered ring having 0-2 heteroatomsselected from oxygen, sulfur, or nitrogen, wherein each substitutablering carbon of said fused ring formed by R^(x) and R^(y) isindependently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

(b) R¹ is T-(Ring D), wherein T is a valence bond or a methylene unit;

(c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclicaryl or heteroaryl ring; and

(d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′) aretaken together to form an optionally substituted benzo ring.

More preferred compounds of formula IVb have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(y) is T—R³ or L—Z—R³ wherein T is a valence bond or a methyleneand R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl; or R^(x) and R^(y) are taken together with theirintervening atoms to form a benzo, pyrido, cyclopento, cyclohexo,cyclohepto, thieno, piperidino, or imidazo ring, wherein eachsubstitutable ring carbon of said fused ring formed by R^(x) and R^(y)is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

(b) R¹ is T-(Ring D), wherein T is a valence bond, and Ring D is a 5-6membered monocyclic or an 8-10 membered bicyclic aryl or heteroarylring;

(c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

(d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—.

Even more preferred compounds of formula IVb have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl,methylamino or acetamido and R^(y) is selected from 2-pyridyl,4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl,ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl,alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido,optionally substituted phenyl, or methoxymethyl; or R^(x) and R^(y) aretaken together with their intervening atoms to form a benzo, pyrido,piperidino, or cyclohexo ring, wherein said ring is optionallysubstituted with —halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN,—O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —NO₂ —N(R⁴)₂, —NR⁴COR, —NR⁴SO₂R, or—SO₂N(R⁴)₂, wherein R is hydrogen or an optionally substituted C₁₋₆aliphatic group;

(b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6membered aryl or heteroaryl ring optionally substituted with one or twogroups selected from —halo, —CN, —NO₂, —N(R⁴)₂, optionally substitutedC₁₋₆ aliphatic, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R,—SO₂N(R⁴)₂, —N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂;

(c) R² is hydrogen or a substituted or unsubstituted group selected fromaryl, heteroaryl, or a C₁₋₆ aliphatic group, and R^(2′) is hydrogen; and(d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl, and L is —O—, —S—, or —NH—; and

(e) Ring D is substituted by up to three substituents selected from—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring.

Representative compounds of formula IVb are shown below in Table 10.

TABLE 10

IVb-1

IVb-2

IVb-3

IVb-4

IVb-5

IVb-6

IVb-7

IVb-8

IVb-9

IVb-10

IVb-11

IVb-12

IVb-13

IVb-14

IVb-15

IVb-16

In another embodiment, this invention provides a composition comprisinga compound of formula IVb and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIVb or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula IVb or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IVb or apharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IVb or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula IVb or a composition comprising saidcompound.

Another method relates to inhibiting Aurora-2 or GSK-3 activity in abiological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IVb, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IVb, asdescribed above.

Another embodiment of this invention relates to compounds of formulaIVc:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z¹ is nitrogen or C—R⁸ and Z² is nitrogen or CH, wherein one of Z¹ or Z²is nitrogen;

R^(x) and R^(y) are independently selected from T—R³ or L—Z—R³, or R^(x)and R^(y) are taken together with their intervening atoms to form afused, unsaturated or partially unsaturated, 5-7 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereineach substitutable ring carbon of said fused ring formed by R^(x) andR^(y) is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

R¹ is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbonof Ring D is independently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

Z is a C₁₋₄ alkylidene chain;

L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R)—;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R^(2′) isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂O, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂.

Preferred rings formed by R^(x) and R^(y) of formula IVc include a 5-,6-, or 7-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.This provides a bicyclic ring system containing a pyridine ring.Preferred pyridine ring systems of formula IVc are shown below.

More preferred pyridine ring systems of formula IVc include IVc-A,IVc-B, IVc-D, IVc-E, IVc-J, IVc-P, and IVc-V, most preferably IVc-A,IVc-B, IVc-D, IVc-E, and IVc-J. Even more preferred pyridine ringsystems of formula IVc are those described above, wherein Z¹ is nitrogenand Z² is CH

Preferred R^(x) groups of formula IVc include hydrogen, alkyl- ordialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

Preferred R^(y) groups of formula IVc include T—R³ or L—Z—R³ wherein Tis a valence bond or a methylene, L is —O—, —S—, or —N(R⁴)—, —C(R⁶)₂O—,—CO— and R³ is —R, —N(R⁴)₂, or —OR. Examples of preferred R^(y) groupsinclude 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl,alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such asmethoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylaminoor dimethylamino, alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy, acetamido, optionally substituted phenyl such asphenyl or halo-substituted phenyl.

The ring formed when the R^(x) and R^(y) groups of formula IVc are takentogether may be substituted or unsubstituted. Suitable substituentsinclude —R, halo, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR,—N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂, —N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁶)CON(R⁶)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, R and R⁴ are as defined above. PreferredR^(x)/R^(y) ring substituents include —halo, —R, —OR, —COR, —CO₂R,—CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂,—NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group.

The R² and R^(2′) groups of formula IVc may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IVc compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IVcinclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄alkyl), —CN, —SO₂(C₁₋₄alkyl),—SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —C(O)NH₂,and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight, branched,or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group is methyl.

When the pyrazole ring system of formula IVc is monocyclic, preferred R²groups include hydrogen or a substituted or unsubstituted group selectedfrom aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples of suchpreferred R² groups include H, methyl, ethyl, propyl, cyclopropyl,i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

When Ring D of formula IVc is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IVc is bicyclic, preferred bicyclic Ring D groupsinclude naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IVc, preferred T—R⁵ or V—Z—R⁵ substituents include—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t—Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

Preferred R⁸ groups of formula IVc, when present, include R, OR, andN(R⁴)₂. Examples of preferred R⁸ include methyl, ethyl, NH₂,NH₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂O, (piperidin-1-yl)CH₂CH₂O,and NH₂CH₂CH₂O.

Preferred formula IVc compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄aliphatic group and R^(y) is T—R³ or L—Z—R³, wherein T is a valence bondor a methylene and R³ is —R, —N(R⁴)₂, or —OR; or R^(x) and R^(y) aretaken together with their intervening atoms to form a fused, unsaturatedor partially unsaturated, 5-6 membered ring having 0-2 heteroatomsselected from oxygen, sulfur, or nitrogen, wherein each substitutablering carbon of said fused ring formed by R^(x) and R^(y) isindependently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

(b) R¹ is T-(Ring D), wherein T is a valence bond or a methylene unit;

(c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclicaryl or heteroaryl ring; and

(d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′) aretaken together to form an optionally substituted benzo ring.

More preferred compounds of formula IVc have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(y) is T—R³ or L—Z—R³ wherein T is a valence bond or a methyleneand R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl; or R^(x) and R^(y) are taken together with theirintervening atoms to form a benzo, pyrido, cyclopento, cyclohexo,cyclohepto, thieno, piperidino, or imidazo ring, wherein eachsubstitutable ring carbon of said fused ring formed by R^(x) and R^(y)is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

(b) R¹ is T-(Ring D), wherein T is a valence bond, and Ring D is a 5-6membered monocyclic or an 8-10 membered bicyclic aryl or heteroarylring;

(c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

(d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—.

Even more preferred compounds of formula IVc have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl,methylamino or acetamido and R^(y) is selected from 2-pyridyl,4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl,ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl,alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido,optionally substituted phenyl, or methoxymethyl; or R^(x) and R^(y) aretaken together with their intervening atoms to form a benzo, pyrido,piperidino, or cyclohexo ring, wherein said ring is optionallysubstituted with —halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN,—O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —NO₂ —N(R⁴)₂, —NR⁴COR, —NR⁴SO₂R, or—SO₂N(R⁴)₂, wherein R is hydrogen or an optionally substituted C₁₋₆aliphatic group;

(b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6membered aryl or heteroaryl ring optionally substituted with one or twogroups selected from —halo, —CN, —NO₂, —N(R⁴)₂, optionally substitutedC₁₋₆ aliphatic, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R,—SO₂N(R⁴)₂, —N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂;

(c) R² is hydrogen or a substituted or unsubstituted group selected fromaryl, heteroaryl, or a C₁₋₆ aliphatic group, and R² is hydrogen; and

(d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl, and L is —O—, —S—, or —NH—; and

(e) Ring D is substituted by up to three substituents selected from—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring.

Representative compounds of formula IVc are shown below in Table 11.

TABLE 11

IVc-1

IVc-2

IVc-3

IVc-4

IVc-5

IVc-6

IVc-7

IVc-8

IVc-9

IVc-10

IVc-11

IVc-12

In another embodiment, this invention provides a composition comprisinga compound of formula IVc and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIVc or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula IVc or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IVc or apharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IVc or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula IVc or a composition comprising saidcompound.

Another method relates to inhibiting Aurora-2 or GSK-3 activity in abiological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IVc, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IVc, asdescribed above.

Another embodiment of this invention relates to compounds of formulaIVd:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z¹ is nitrogen or C—R⁸ and Z²is nitrogen or CH, wherein one of Z¹ or Z²is nitrogen;

Q′ is selected from —C(R^(6′))₂—, 1,2-cyclopropanediyl,1,2-cyclobutanediyl, or 1,3-cyclobutanediyl;

R^(x) and R^(y) are independently selected from T—R³ or L—Z—R, or R^(x)and R^(y) are taken together with their intervening atoms to form afused, unsaturated or partially unsaturated, 5-7 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereineach substitutable ring carbon of said fused ring formed by R^(x) andR^(y) is independently substituted by oxo, T—R³, or L—Z—R³ and eachsubstitutable ring nitrogen of s aid ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

R¹ is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbonof Ring D is independently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q′ is—C(R⁶)₂— a methylene group of said C₁₋₄ alkylidene chain is optionallyreplaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—, —SO₂—, —SO₂NH—,—NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;

Z is a C₁₋₄ alkylidene chain;

L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R^(2′) isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₁₋₆ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R )CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R^(6′) is independently selected from hydrogen or a C₁₋₄ aliphaticgroup, or two R^(6′) on the same carbon atom are taken together to forma 3-6 membered carbocyclic ring;

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂.

Preferred rings formed by R^(x) and R^(y) of formula IVd include a 5-,6-, or 7-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.This provides a bicyclic ring system containing a pyridine ring.Preferred pyridine ring systems of formula IVa are shown below.

More preferred pyridine ring systems of formula IV-d include IVd-A,IVd-B, IVd-D, IVd-E, IVd-J, IVd-P, and IVd-V, most preferably IVd-A,IVd-B, IVd-D, IVd-E, and IVd-J. Even more preferred pyridine ringsystems of formula IVd include those described above, wherein Z¹ isnitrogen and Z² is CH.

Preferred R^(x) groups of formula IVd include hydrogen, alkyl- ordialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

Preferred R^(y) groups of formula IVd include T—R³ or L—Z—R³ wherein Tis a valence bond or a methylene, L is —O—, —S—, or —N(R⁴)—, —C(R⁶)₂O—,—CO— and R³ is —R, —N(R⁴)₂, or —OR. Examples of preferred R^(y) groupsinclude 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl,alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such asmethoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylaminoor dimethylamino, alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy, acetamido, optionally substituted phenyl such asphenyl or halo-substituted phenyl.

The ring formed when the R^(x) and R^(y) groups of formula IVd are takentogether may be substituted or unsubstituted. Suitable substituentsinclude —R, halo, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR,—N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂, —N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴Y₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, R and R⁴ are as defined above. PreferredR^(x)/R^(y) ring substituents include —halo, —R, —OR, —COR, —CO₂R,—CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂,—NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group.

The R² and R^(2′) groups of formula IVd may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IVd compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IVdinclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄alkyl), —CN, —SO₂(C₁₋₄alkyl),—SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —C(O)NH₂,and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight, branched,or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group is methyl.

When the pyrazole ring system of formula IVd is monocyclic, preferred R²groups include hydrogen or a substituted or unsubstituted group selectedfrom aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples of suchpreferred R² groups include H, methyl, ethyl, propyl, cyclopropyl,i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

When Ring D of formula IVd is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IVd is bicyclic, preferred bicyclic Ring D groupsinclude naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IVd, preferred T—R⁵ or V—Z—R⁵ substituents include—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, an—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t—Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

Preferred R⁸ groups of formula IVd, when present, include R, OR, andN(R⁴)₂. Examples of preferred R⁸ include methyl, ethyl, NH₂,NH₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂O, (piperidin-1-yl)CH₂CH₂O,and NH₂CH₂CH₂O.

Preferred Q′ groups of formula IVd include —C(R^(6′))₂— or1,2-cyclopropanediyl, wherein each R^(6′) is independently selected fromhydrogen or methyl. A more preferred Q′ group is —CH₂—.

Preferred formula IVd compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄aliphatic group and R^(y) is T—R³ or L—Z—R³, wherein T is a valence bondor a methylene and R³ is —R, —N(R⁴)₂, or —OR; or R^(x) and R^(y) aretaken together with their intervening atoms to form a fused, unsaturatedor partially unsaturated, 5-6 membered ring having 0-2 heteroatomsselected from oxygen, sulfur, or nitrogen, wherein each substitutablering carbon of said fused ring formed by R^(x) and R^(y) isindependently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

(b) R¹ is T-(Ring D), wherein T is a valence bond or a methylene unitand wherein said methylene unit is optionally replaced by —O—, —NH—, or—S—;

(c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclicaryl or heteroaryl ring; and

(d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′) aretaken together to form an optionally substituted benzo ring.

More preferred compounds of formula IVd have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(y) is T—R³ or L—Z—R³ wherein T is a valence bond or a methyleneand R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl; or R^(x) and R^(y) are taken together with theirintervening atoms to form a benzo, pyrido, cyclopento, cyclohexo,cyclohepto, thieno, piperidino, or imidazo ring, wherein eachsubstitutable ring carbon of said, fused ring formed by R^(x) and R^(y)is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

(b) R¹ is T-(Ring D), wherein T is a valence bond, and Ring D is a 5-6membered monocyclic or an 8-10 membered bicyclic aryl or heteroarylring;

(c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring;

(d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—; and

(e) Q′ is —C(R^(6′))₂— or 1,2-cyclopropanediyl, wherein each R^(6′) isindependently selected from hydrogen or methyl.

Even more preferred compounds of formula IVd have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl,methylamino or acetamido and R^(y) is selected from 2-pyridyl,4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl,ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl,alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido,optionally substituted phenyl, or methoxymethyl; or R^(x) and R^(y) aretaken together with their intervening atoms to form a benzo, pyrido,piperidino, or cyclohexo ring, wherein said ring is optionallysubstituted with —halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN,—O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —NO₂ —N(R⁴)₂, —NR⁴COR, —NR⁴SO₂R, or—SO₂N(R⁴)₂, wherein R is hydrogen or an optionally substituted C₁₋₆aliphatic group;

(b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6membered aryl or heteroaryl ring optionally substituted with one or twogroups selected from —halo, —CN, —NO₂, —N(R⁴)₂, optionally substitutedC₁₋₆ aliphatic, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R,—SO₂N(R⁴)₂, —N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂;

(c) R² is hydrogen or a substituted or unsubstituted group selected fromaryl, heteroaryl, or a C₁₋₆ aliphatic group, and R^(2′) is hydrogen; and

(d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl, and L is —O—, —S—, or —NH—;

(e) Ring D is substituted by up to three substituents selected from—halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group,—OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring; and

(f) Q′ is —CH₂—.

Representative compounds of formula IVd are shown below in Table 12.

TABLE 12

IVd-1

IVd-2

IVd-3

IVd-4

IVd-5

IVd-6

IVd-7

IVd-8

In another embodiment, this invention provides a composition comprisinga compound of formula IVd and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIVd or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula IVd or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a GSK-3-mediated disease with a GSK-3 inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IVd or apharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IVd or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, which method comprises administering to thepatient a compound of formula IVd or a composition comprising saidcompound.

Another method relates to inhibiting Aurora-2 or GSK-3 activity in abiological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula Ivd, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IVd, asdescribed above.

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art for analogous compounds, asillustrated by the general Schemes I-VII, the general-methods thatfollow, and by the preparative examples below.

Reagents: (a) EtOH, Et₃N, room temperature; (b) R¹—QH (Q═S, NH or O) orR¹—CH₂—M/catalyst (M is Al or Mg or Sn, catalyst═Pd° or Ni°)

Scheme I above shows a general route for the preparation of the presentcompounds. The dichlorinated starting material 1 may be prepared usingmethods similar to the those reported in J. Indian. Chem. Soc., 61,690-693 (1984) or in J. Med. Chem., 37, 3828-3833 (1994). The reactionof 1 with aminopyrazole (or aminoindazole) 2 in a manner as described inBioorg. Med. Chem. Lett, 10, 11, 1175-1180, (2000) or in J. Het. Chem,21, 1161-1167, (1984) provides the versatile monochloro intermediate 3.Conditions for displacing the chloro group of 3 by R¹—Q will depend onthe nature of the Q linker moiety and are generally known in the field.See, for example, J. Med. Chem, 38, 14, 2763-2773, (1995) (where Q is anN-Link), or Chem. Pharm. Bull., 40, 1, 227-229, (1992) (S-Link), or J.Het. Chem., 21, 1161-1167, (1984) (O-Link) or Bioorg. Med. Chem. Lett,8, 20, 2891-2896, (1998) (C-Link).

Reagents: (a) POCl₃, Pr₃N, 110° C.; (b) EtOH, Et₃N, room temperature.

Scheme II above shows an alternative route for the preparation of thepresent compounds. The starting material 4 may be prepared in a mannersimilar to that described for analogous compounds. See Chem. Heterocycl.Compd., 35, 7, 818-820 (1999) (where Q is an N-Link), Indian J. Chem.Sect. B. 22, 1, 37-42 (1983) (N-Link), Pestic. Sci, 47, 2, 103-114(1996) (O-Link), J. Med. Chem., 23, 8, 913-918 (1980) (S-Link), orPharmazie, 43, 7, 475-476 (1988) (C-Link). The chlorination of 4provides intermediate 5. See J. Med. Chem., 43, 22, 4288-4312 (2000) (Qis an N-Link), Pestic. Sci, 47, 2, 103-114 (1996) (O-Link), J. Med.Chem., 41, 20, 3793-3803 (1998) (S-Link), or J. Med. Chem., 43, 22,4288-4312 (2000) (C-Link). Displacement of the 4-Cl group inintermediate 5 with aminopyrazole (or aminoindazole) 2 to providecompounds of this invention may be performed according to known methodsfor analogous compounds. See J. Med. Chem., 38, 14, 2763-2773 (1995)(where Q is an N-Link), Bioorg. Med. Chem. Lett ., 7 , 4, 421-424 (1997)(O-Link), Bioorg. Med. Chem. Lett., 10, 8, 703-706 (2000) (S-Link), orJ. Med. Chem., 41, 21, 4021-4035 (1998) (C-Link).

Reagents: (a) POCl₃; (b) EtOH, Et₃N, room temperature; (c) Oxone; (d)R¹—QH (Q═S, NH or O) or R¹—CH₂—M/catalyst (M is Al or Mg or Sn,catalyst═Pd° or Ni°)

Scheme III above shows another alternative route for preparing thepresent compounds. The starting material 6 may be chlorinated to provideintermediate 7. Displacement of the 4-chloro group in 7 withaminopyrazole (or aminoindazole) 2 gives intermediate 8 which, uponoxidation of the methylsulfanyl group, provides the methylsulfone 9. Themethylsulfonyl group of 9 may be displaced readily with R¹—QH to givethe desired product I. See J. Am. Chem. Soc., 81, 5997-6006 (1959)(where Q is an N-Link) or in Bioorg. Med. Chem. Lett., 10, 8, 821-826(2000) (S-Link).

Reagents: (a) POCl₃; (b) EtOH, Et₃N, room temperature; (c) R^(y)—H (R═S,NH or O); (d) oxone; (e) R¹—QH (Q═S, NH or O) or R—CH₂—M/catalyst (M isAl or Mg or Sn catalyst═Pd° or Ni°)

Scheme IV above shows a general route for the preparation of the presentcompounds wherein R^(y) is a group attached to the pyrimidine core via anitrogen, oxygen or sulfur heteroatom. The starting 4,6-dihydroxy-2-methylsulfanylpyrimidine 10 may be prepared as describedin J. Med. Chem., 27, 12, 1621-1629 (1984). The chloro groups ofintermediate 11 may be displaced sequentially with aminopyrazole (oraminoindazole) 2 and then with another amine (or alcohol or thiol)following procedures similar to those reported in U.S. Pat. No.2,585,906 (ICI, 1949). The methylsulfanyl group of 13 may then beoxidized to provide the methylsulfone 14. Displacement of themethylsulfonyl group of 14 gives the desired product II.

Scheme V above shows general routes for the preparation of compounds offormulae IVa, IVb, IVc, and Ivd. Steps (a) and (b) are analogous to thecorresponding steps described in Scheme I above. See Indian J. Chem.Sect. B, 34, 9, 1995, 778-790; J. Chem. Soc., 1947, 899-905; J. Chem.Soc., 34, 9, 1948, 777-782; and Indian J. Chem., 1967, 467-470.

The synthetic transformations shown in Schemes I-IV above are furtherillustrated by the following methods.

Scheme VI above shows a general route for preparing the aryl guanidineintermediate used to prepare compounds where Q is —C(R^(6′))₂—. Themono- or bis-alkylation of 19 at step (a) to prepare compound 20 can beachieved by using methods substantially similar to those described byJeffery, J. E., et al, J. Chem Soc, Perkin Trans 1, 1996 (21) 2583-2589;Gnecco, D., et al, Org Prep Proced Int, 1996, 28 (4), 478-480;Fedorynski, M. and Jonczyk, A., Org Prep Proced Int, 1995, 27 (3),355-359; Suzuki, S, et al, Can J Chem, 1994, 71 (2) 357-361; and Prasad,G., et al, J Org Chem, 1991, (25), 7188-7190. The method of step (b) toprepare compound 21 from compound 20 can be achieved by using methodssubstantially similar to those described by Moss, R., et is al,Tetrahedron Lett, 1995, (48), 8761-8764 and Garigipati, R., TetrahedronLett, 1990, (14), 1969-1972.

The aryl guanidine intermediates prepared according to Scheme VI maythen be used to prepare the compounds of this invention by the methodsdescribed in the above Schemes I-V and by methods known to one skilledin the art.

Scheme VII above shows a general method that may be used to preparecompounds of formula II wherein Q is 1,2-cyclopropanediyl. Compound 26may then be used to prepare the desired amino-pyrazole compounds usingthe methods described above at Scheme I step (b).

Method A. To a solution of 2,4-dichloroquinazoline (12.69 g, 63 mmol)and 3-amino-5-methylpyrazole (6.18 g, 63 mmol) in ethanol (220 mL) isadded triethylamine (8.13 mL, 63 mmol) and the reaction mixture isstirred for 3 hours at room temperature. The pale yellow precipitate isthen collected by filtration, washed with cold ethanol and dried undervacuum to give(2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.

The above-prepared(2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (155 mg, 0.6mmol) and 3-chloroaniline (0.316 mL, 2.99 mmol) are refluxed intert-butanol (3 mL) over 20 h. The mixture is concentrated in vacuo andthe residue is suspended in EtOH/H₂O (1 mL/3 mL). K₂CO₃ (83 mg, 0.6mmol) is added and the suspension is stirred for 2 h at roomtemperature. The solid that forms is collected and dried under vacuum togive the product[2-(3-chlorophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

Method B. Sodium hydride (45 mg, 1.12 mmol) in THF (2 mL) is treatedwith 3-methoxyphenol (0.94 g, 7.6 mmol) and the reaction mixture isstirred until effervescence ceases. The THF is removed in vacuo and theabove-prepared(2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (150 mg, 0.51mmol)) is added. The reaction mixture is stirred at 100° C. for 20 h,then poured into aqueous K₂CO₃ and stirred for 2 h at room temperature.The solid that forms is collected and re-crystallized from ethanol togive the product[2-(3-methoxyphenoxy)-qainazolin-4yl]-(5-methyl-2H-pyrazol-3-yl)-amine

Method C. To a solution of 4-hydroxy-2-phenoxymethylquinazoline (2 g,7.93 mmol) in phosphorus oxychloride (10 mL) is added tripropylamine(3.02 mL, 15.8 mmol) and the reaction mixture is heated for 30 minutesat 110° C. The excess phosphorus oxychloride is evaporated in vacuo, theresidue is poured on ice cold aqueous NaHCO₃ and extracted with ethylacetate. The organic layer is washed with brine, dried, filtered andevaporated. The resulting residue is purified on flash chromatography(SiO₂, hexane /AcOEt gradient) to give4-chloro-2-phenoxymethylquinazoline.

To a solution of the above 4-chloro-2-phenoxymethylquinazoline (0.5 g,1.85 mmol) in THF (30 mL) is added 3-amino-5-cyclopropylpyrazole (0.47g, 3.69 mmol) and the reaction mixture is heated at 65° C. for 24 hours.Solvent is evaporated and ethanol is added. A white solid forms and iscollected by filtration and dried under vacuum to give(5-cyclopropyl-2H-pyrazol-3-yl)-(2-phenoxymethyl-quinazolin-4-yl)-amine.

Method D. To a solution of the above-prepared(2-chloroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (123 mg,0.43 mmol) in THF (5 mL) is added NiCl₂(dppp) (12 mg, 2.1.10⁻⁵ mol),followed by 1M benzylmagnesium chloride in THF (2.15 mL, 2.15 mmol). Thesolution is heated at 50° C. for 20 hours and the reaction mixture isthen quenched with aqueous NH₄Cl and the product extracted in ethylacetate. The solvent is evaporated and the residue purified by flashchromatography to yield the desired(2-benzyl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.

Method E. A solution of(2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (200 mg, 0.77mmol) and 4-acetamidothiophenol (644 mg, 3.85 mmol) is refluxed intert-butanol (3 mL) over a 20 hour period. Diethylether (10 mL) is addedto the mixture and a solid forms that is collected by filtration. Thissolid is suspended in EtOH/H₂O 1 mL/3 mL), then K₂CO₃ (110 mg, 0.8 mmol)is added and the suspension is stirred for 2 h at room temperature. Asolid forms and is collected and dried under vacuum to give the product[2-(4-acetamidophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

Method F. To a solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline(500 mg, 2.46 mmol) and 3-amino-5-cyclopropylpyrazole (303 mg, 2.46mmol) in DMF (10 mL) is added triethylamine (0.357 mL, 2.56 mmol)followed by sodium iodide (368 mg, 2.46 mmol) and the reaction mixtureis heated at 90° C. for 20 h. The reaction mixture is partitionedbetween ethyl acetate and aqueous saturated NaHCO₃. The organic layer iswashed with brine and evaporated in vacuo. The residue is purified byflash chromatography (SiO₂, hexane/AcOEt gradient) to give(2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.

The above-prepared(2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amineis reacted with 2-naphthalene mercaptan as described in Method L toyield the desired(5-cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-ylsulfanyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine.

Method G. A solution of(5-cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-amine(110 mg, 0.26 mmol) in a mixture of THF/water (1/1, 10 mL) is treatedwith 1M LiOH (0.75 mL, 0.75 mmol). The mixture is stirred for 20 hoursat room temperature and then neutralized with 1M HCl (0.75 mL, 0.75mmol). A solid forms and is collected by filtration to afford thedesired[2-(3-carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.

Method H. A solution of[2-(4-acetamidophenylsulfanyl)-7-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(23 mg, 5.54.10⁻⁵ mol) in dichloroethane (3 mL) is treated with 1M BBr₃in dichloromethane (222 μL, 2.21.10⁻⁴ mol). The mixture os heated at 80°C. for 4 hours before 1M BBr₃ in DCM (222 μL, 2.21.10⁻⁴ mol) is added.The reaction mixture is heated at 80° C. for a further 3 hours. Thesolvent is evaporated and methanol is added to the residue to quenchresidual BBr₃. The solvent is evaporated in vacuo and this operationrepeated 3 times. 1M HCl (2 mL) is added to the solid residue and thesuspension stirred at room temperature for 15 hours. The solid iscollected by filtration and suspended in a mixture water/EtOH (3/1, 8mL). The mixture is neutralized with NaHCO₃ and stirred for 2 hours atroom temperature. The solid is then collected by filtration, rinsed withwater and diethyl ether to give the desired[2-(4-acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl-amine.

Method I. To a solution of[2-(4-acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(32 mg, 7.87.10⁻⁵ mol) in DMF (1 mL) is added potassium carbonate (65mg, 4.72.10⁻⁴ mol) and the reaction mixture is heated to 80° C.N-(3-chloropropyl)morpholine (39 mg, 2.36.10⁻⁴ mol) is then added, andthe mixture is stirred at 80° C. for 4 hours, cooled to room temperatureand the solvent is evaporated. The resulting residue is purified byflash chromatography to afford the desired[2-(4-acetamidophenylsulfanyl)-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

Method J. To a solution of[2-(4-acetamido-phenylsulfanyl)-7-nitroquinazolin-4-yl]-(S-methyl-2H-pyrazol-3-yl)-amine(147 mg, 3.38.10⁻⁴ mol) in methanol (5 mL) is added Pd/C 10% (40 mg) andthe reaction mixture is treated with hydrogen at balloon pressure at 45°C. for 20 hours. The catalyst is filtered through a pad of celite whichis then washed with dilute HCl. The combined yellow filtrate isevaporated and the resulting solid residue is crystallized from methanolto afford the desired[2-(4-acetamido-phenylsulfanyl)-7-hydroxyaminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

Method K.[2-(4-Acetamido-phenylsulfanyl)-7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(182 mg, 4.18.10⁻⁴ mol) is dissolved in a mixture EtOH/water/AcOH(25/10/1, 36 mL) and the reaction is heated at 90° C. Iron powder (93mg) is added and the mixture is stirred at 90° C. for 4 hours, cooled toroom temperature and filtered through a pad of celite. The pad is washedwith methanol and the combined filtrate is concentrated in vacuo. Theresidue is purified by flash chromatography (SiO₂, DCM/MeOH gradient) togive the desired[2-(4-acetamido-phenylsulfanyl)-7-aminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

Method L. To a solution of 2,4-dichloro-6-phenyl-pyrimidine (300 mg,1.33 mmol) and 3-amino-5-methylpyrazole (129 mg, 1.33 mmol) in DMF (7mL) is added triethylamine (195 μL, 1.40 mmol) followed by sodium iodide(200 mg, 1.33 mmol) and the reaction mixture is stirred for 15 hours at90° C. The resulting solution is partitioned between ethyl acetate andwater and the organic phase washed with brine, dried over MgSO₄ thenconcentrated in vacuo. The residue is triturated in methanol and theresulting white solid collected by filtration to afford(2-chloro-6-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (236mg, 62%).

The above prepared(2-chloro-6-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (60mg, 0.21 mmol) is combined with 4-acetamidothiophenol (176 mg, 1.05mmol) in tert-butanol (5 mL) and the mixture heated at reflux for 20hours. The reaction mixture is cooled to room temperature andpartitioned between ethyl acetate and aqueous NaHCO₃. The organic layeris washed with brine, dried over MgSO₄ and concentrated in vacuo. Theresulting residue is purified by flash chromatography (SiO₂, DCM/MeOHgradient) to afford[2-(4-acetamido-phenylsulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(74 mg, 85%)

Method M. To a suspension of 4,6-dihydroxymercaptopyrimidine (8 g, 55mmol) in a mixture of EtOH/water (1/1, 140 mL) is added NaOH (2.33 g,58.3 mmol) followed by 4-methoxybenzyl chloride (7.90 mL, 58.3 mmol).The solution is stirred for 1.5 hours at 60° C. and then at roomtemperature for a further 6 hours. The resulting white precipitate iscollected by filtration to give4,6-dihydroxy-2-(4-methoxy-benzylsulfanyl)-pyrimidine.

The above-prepared 4,6-dihydroxy-2-(4-methoxy-benzylsulfanyl)-pyrimidine(2.5 g, 9.46 mmol) is suspended in POCl₃ (20 mL), and tripropylamine(3.60 mL, 18.9 mmol) is added dropwise to the mixture. The reaction isthen heated at 110° C. for 4 hours. The brown solution is cooled to roomtemperature and the solvent is evaporated. The residue is poured on icecold NaHCO₃ and the product is then extracted with ethyl acetate. Theorganic phase is dried over MgSO₄, concentrated in vacuo and the residueis purified by flash chromatography (SiO₂, hexane/AcOEt gradient) togive 4,6-dichloro-2-(4-methoxy-benzylsulfanyl)-pyrimidine.

To a solution of above-prepared4,6-dichloro-2-(4-methoxy-benzylsulfanyl)-pyrimidine (915 mg, 3.04 mmol)and 3-amino-5-methylpyrazole (310 mg, 3.19 mmol) in BuOH (20 mL) isadded diisopropylethylamine (0.56 mL, 3.19 mmol) followed by sodiumiodide (455 mg, 3.04 mmol). The reaction mixture is stirred for 15 hoursat 120° C. The solvent is removed in vacuo and the residue is purifiedby flash chromatography (SiO₂, hexane/AcOEt gardient) to give[6-chloro-2-(4-methoxy-benzylsulfanyl)-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.

The above-prepared[6-chloro-2-(4-methoxy-benzylsulfanyl)-pyrimidin-4-yl)-(S-methyl-2H-pyrazol-3-yl)-amine(500 mg, 1.38 mmol) in 1-methylpiperazine (10 mL) is heated at 130° C.for 15 hours. The solvent is then removed in vacuo and the residue ispurified by flash chromatography (SiO₂, dichloromethane/MeOH gradient)to give the desired product(2-(4-methoxy-benzylsulfanyl)-6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

Method N. A solution of[2-(4-acetamido-phenyl-sulfanyl)-6-(4-methoxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(100 mg, 2.24.10⁻⁴ mol) in dichloroethane (5 mL) is treated with 1M BBr₃in DCM (896 μL, 8.96.10⁻⁴ mol). The mixture is then heated at 80° C. for4 hours before 1M BBr₃ in DCM (896 μL, 8.96.10⁻⁴ mol) is added. Thereaction mixture is then heated at 80° C. for a further 3 hours. Thesolvent is evaporated and methanol is added to the residue to quench anyresidual BBr₃. The solvent is evaporated in vacuo and this evaporationstep is repeated 3 times. 1M HCl(8 mL) is added to the solid residue andthe suspension is stirred at room temperature for 15 hours. The solid iscollected by filtration and suspended in a mixture of water/EtOH (3/1,24 mL). The mixture is neutralized with NaHCO₃ and stirred for 2 hoursat room temperature. The solid is then collected by filtration, rinsedwith water and with diethyl ether to give[2-(4-acetamido-phenyl-sulfanyl)-6-(4-hydroxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

To a solution of the above-prepared[2-(4-acetamido-phenyl-sulfanyl)-6-(4-hydroxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(70 mg, 1.62.10⁻⁴ mol) in DMF (3 mL) is added potassium carbonate (134mg, 9.71.10⁻⁴ mol). The reaction mixture is heated to 80° C. before1-dimethylamino-3-chloropropane hydrochloride (77 mg, 4.86.10⁻⁴ mol) isadded. The mixture is stirred at 80° C. for 4 hours, cooled to roomtemperature and the solvent is evaporated. The residue is purified byflash chromatography to afford the desired product{2-(4-acetamido-phenyl-sulfanyl)-6-[4-(3-dimethylamino-propoxy)-phenyl]-pyrimidin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine.

Method O. To a solution of[6-methoxycarbonyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(2 g, 4.85 mmol) in THF (100 mL) is added lithium borohydride (0.32 g,14.5 mmol). The reaction mixture is stirred at 50° C. for 1.5 hours. Thereaction is then quenched with dilute HCl and extracted with ethylacetate. The organic layer is successively washed with aqueous saturatedNaHCO₃ and brine, dried over MgSO₄ and evaporated. The solid residue istriturated in ethyl acetate and the resulting white solid is collectedby filtration to give the desired product[6-hydroxymethyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

Method P. To a solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine (5g, 25.6 mmol) and 3-amino-5-methylpyrazole 2.61 g, 26.9 mmol) in BuOH(60 mL) is added diisopropylethylamine (4.69 mL, 26.9 mmol) followed bysodium iodide (3.84 g, 25.6 mmol). The reaction mixture is stirred for15 hours at 120° C. The solvent is then removed in vacuo and the residueis purified by flash chromatography (SiO₂, hexane/AcOEt gradient) togive[6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.

The above-prepared[6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(2.42 g, 9.46 mmol) is heated in morpholine (10 mL) at 130° C. for 15hours. The solvent is then removed in vacuo and the solid residue istriturated in EtOH and collected by filtration to give[2-methylsulfanyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

To a suspension of the above-prepared[2-methylsulfanyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(500 mg, 1.63 mmol) in MeOH (10 mL) is added a solution of oxone (3.0 g)in water (10 mL). The reaction mixture is stirred at room temperaturefor 15 hours and most of the solvent is evaporated. The residue ispartitioned between DCM and aqueous saturated NaHCO₃. The organic layeris washed with brine, dried, filtered and evaporated. The residue istriturated in MeOH and the resulting white solid is collected byfiltration to give[2-methylsulfonyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

The above-prepared[2-methylsulfonyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(178 mg, 0.52 mmol) and 4-acetamidothiophenol (176 mg, 1.05 mmol) arerefluxed in tert-butanol (5 mL) over 20 h. The reaction mixture iscooled to room temperature and partitioned between ethyl acetate andaqueous NaHCO₃. The organic layer is washed with brine, dried over MgSO₄and concentrated in vacuo. The residue is purified by flashchromatography to give the desired product[2-(4-acetamidophenylsulfanyl)-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

SYNTHETIC EXAMPLES

The following HPLC methods were used in the analysis of the compounds asspecified in the Synthetic Examples set forth below. As used herein, theterm “R_(t)” refers to the retention time observed for the compoundusing the HPLC method specified.

HPLC-Method A:

Column: C18, 3 um, 2.1×50 mm, “Lighting” by Jones Chromatography.

Gradient: 100% water (containing 1% acetonitrile, 0.1% TFA) to 100%acetonitrile (containing 0.1% TFA) over 4.0 min, hold at 100%acetonitrile for 1.4 min and return to initial conditions. Total runtime 7.0 min. Flow rate: 0.8 mL/min.

HPLC-Method B:

Column: C18, 5 um, 4.6×150 mm “Dynamax” by Rainin Gradient: 100% water(containing 1% acetonitrile, 0.1% TFA) to 100% acetonitrile (containing0.1% TFA) over 20 min, hold at 100% acetonitrile for 7.0 min and returnto initial conditions. Total run time 31.5 min. Flow rate: 1.0 mL/min.

HPLC-Method C:

Column: Cyano, 5 um, 4.6×150 mm “Microsorb” by Varian.

Gradient: 99% water (0.1% TFA), 1% acetonitrile (containing 0.1% TFA) to50% water (0.1% TFA), 50% acetonitrile (containing 0.1% TFA) over 20min, hold for 8.0 min and return to initial conditions. Total run time30 min. Flow rate: 1.0 mL/min.

HPLC-Method D:

Column: Waters (YMC) ODS-AQ 2.0×50 mm, S5, 120A.

Gradient: 90% water (0.2% Formic acid), 10% acetonitrile (containing0.1% Formic acid) to 10% water (0.1% formic acid), 90% acetonitrile(containing 0.1% formic acid) over 5.0 min, hold for 0.8 min and returnto initial conditions. Total run time 7.0 min.

Flow rate: 1.0 mL/min.

HPLC-Method E:

Column: 50×2.0 mm Hypersil C18 BDS;5 μm

Gradient: elution 100% water (0.1% TFA), to 5% water (0.1% TFA), 95%acetonitrile (containing 0.1% TFA) over 2.1 min, returning to initialconditions after 2.3 min.

Flow rate: 1 mL/min.

Example 1(5-Methyl-2H-pyrazol-3-yl)-(2-phenylsulfanyl-quinazolin-4-yl)-amine(IIa-1):

Prepared in a manner similar to the above described Method E to afford apale yellow solid, mp >300° C. (dec.); ¹H NMR (DMSO) δ2.07(3H, s),5.54(1H, s), 7.38(1H, m), 7.56-7.45(4H, m), 7.65(2H, m), 7.73 (1H, m),8.55(1H, d), 10.43(1H, s), 12.05(1H, br s); IR (solid) 3259, 3170, 3109,1618, 1594, 1565, 1525, 1476; MS 334.0 (M+H)⁺

Example 2[2-(4-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-2):

Prepared in a manner similar to the above described Method E to afford apale yellow solid, mp 259-260° C.; ¹H NMR (DMSO) δ2.12 (3H, s), 5.40(1H, s), 7.60 (1H, t), 7.64 (2H, d), 7.76 (3H, d), 7.92 (1H, t), 8.70(1H, d) 11.50 (1H, br s); IR (solid) 1627, 1606, 1557, 1484, 1473, 1433,1400, 1339, 1286, 1219; MS 368.0 (M+H)⁺

Example 3[2-(2,4-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-3):

Prepared in a manner similar to the above described Method E to afford apale yellow solid, mp 258-259° C.; ¹H NMR (DMSO) δ2.12 (3H, s), 5.40(1H, s), 7.54 (1H, t), 7.63 (1H, m), 7.68 (1H, d), 7.86 (1H, t), 7.92(1H, d), 7.96 (1H, d), 8.66 (1H, d) 11.20 (1H, br s); IR (solid) 1623,1610, 1551, 1488, 1435, 1410, 1339, 1284, 1217; MS 402.0 (M+H)⁺

Example 4[2-(4-Methoxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-4):

Prepared in a manner similar to the above described Method E to afford apale yellow solid, mp 264-268° C.; ¹H NMR (DMSO) δ2.04 (3H, s), 3.85(3H, s), 5.43 (1H, s), 7.12 (2H, d), 7.53 (1H, t), 7.61 (3H, d), 7.84(3H, t), 8.63 (1H, d), 11.09 (1H, br s), 12.30 (1H, br s); IR (solid)1622, 1598, 1552, 1492, 1404, 1340, 1292, 1249, 1219, 1171, 1161; MS364.1 (M+H)⁺

Example 5[2-(2-Ethylphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-5):

Prepared in a manner similar to the above described Method E to afford apale yellow solid, mp 205-208° C.; ¹H NMR (DMSO) δ2.05 (3H, s), 5.19(1H, s), 7.38 (1H, t), 7.52-7.64 (3H, m), 7.68 (2H, d), 7.90 (1H, t),8.68 (1H, d); IR (solid) 3262, 2967, 1632, 1605, 1558, 1492, 1434, 1403,1344, 1294, 1224, 1162; MS 362.1 (M+H)⁺

Example 6{2-[2,4-Bis(trifluoromethyl)phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-6):

Prepared in a manner similar to the above described Method E to afford apale yellow solid, mp >300° C.; ¹H NMR (DMSO) δ1.98 (3H, S), 5.37 (1H,S), 7.50 (1H, t), 7.59 (2H, d), 7.84 (1H, d), 8.32 (1H, s), 8.40 (2H,s), 8.66 (1H, d), 10.73 (1H, br s); IR (solid) 1628, 1603, 1577, 1548,1512, 1493, 1448, 1417, 1354, 1275, 1196, 1124; MS 470.1 (M+H)⁺

Example 7[2-(2-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-7):

Prepared in a manner similar to the above described Method E to afford apale yellow solid, mp 262-263° C.; ¹H NMR (DMSO) δ2.05 (3H, s), 5.35(1H, s), 7.52 (2H, t), 7.65 (2H, m), 7.74 (1H, d), 7.83 (1H, t), 7.88(1H, d), 8.62 (1H, d), 10.97 (1H, br s); IR (solid) 1621, 1603, 1569,1544, 1491, 1448, 1400, 1376, 1336, 1288, 1208; MS 368.0 (M+H)⁺

Example 8[2-(2,3-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-8):

Prepared in a manner similar to the above described Method E to afford apale yellow solid, mp >300° C.; ¹H NMR (DMSO) δ2.05 (3H, s), 5.34 (1H,s), 7.50 (2H, m), 7.60 (1H, d), 7.75 (1H, t), 7.88 (2H, m), 8.62 (1H,d), 10.72 (1H, br s); IR (solid) 1632, 1609, 1561, 1532, 1492, 1432,1400, 1380, 1345, 1298, 1228, 1162, 1125; MS 402.0 (M+H)⁺

Example 9[2-(3-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-9):

Prepared in a manner similar to the above described Method E to afford apale yellow solid, mp 248-249° C.; ¹H NMR (DMSO) δ2.05 (3H, s), 5.42(1H, s), 7.55 (2H, m), 7.66 (3H, m), 7.81 (1H, s), 7.85 (1H, t), 8.62(1H, d), 11.10 (1H, br s); IR (solid) 1628, 1611, 1551, 1487, 1432,1410, 1341, 1292, 1217, 1165; MS 368.0 (M+H)⁺

Example 10[2-(1-Methylimidazol-2-ylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-10):

Prepared in a manner similar to the above described Method E to affordan off white solid, mp 255-256° C.; ¹H NMR (DMSO) δ2.19 (3H, s), 3.59(1H, s), 5.51 (1H, s), 7.18 (1H, s), 7.45 (1H, t), 7.57 (1H, s), 7.59(1H, d), 7.77 (1H, t), 8.57 (1H, d), 10.57 (1H, s), 12.13 (1H, br s); IR(solid) 1628, 1565, 1550, 1532, 1492, 1430, 1376, 1333, 1292, 1278,1211; MS 338.2 (M+H)⁺

Example 11[2-(2-Hydroxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-11):

Prepared in a manner similar to the above described Method E to afford apale yellow solid, mp 273-275° C.; ¹H NMR (DMSO) δ2.06 (3H, s), 5.41(1H, s), 6.99 (1H, t), 7.07 (1H, d), 7.50 (1H, t), 7.57-7.62 (2H, m),7.73 (1H, d), 7.94 (1H, t), 8.71 (1H, d), 10.29 (1H, br s), 11.66 (1H,br s); IR (solid) 1623, 1597, 1552, 1485, 1442, 1404, 1354, 1341, 1289,1221, 1165; MS 350.1 (M+H)⁺

Example 12[2-(2,4-Difluorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-12):

Prepared in a manner similar to the above described Method E to afford apale yellow solid, mp 256-258° C.; ¹H NMR (DMSO) 2.10 (3H, s), 5.41 (1H,s), 7.33 (1H, t), 7.51-7.58 (2H, m), 7.65 (1H, d), 7.82-7.91 (2H, m),8.63 (1H, d), 11.06 (1H, br s); IR (solid) 1626, 1608, 1556, 1482, 1409,1341, 1288, 1270, 1219, 1162, 1140; MS 370.1 (M+H)⁺

Example 13[2-(3,4-Dimethoxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-13):

Prepared in a manner similar to the above described Method E to afford apale yellow solid, mp 229-232° C.; 1H NMR (DMSO) δ2.05 (3H, s), 3.70(3H, s), 3.85 (3H, s), 5.39 (1H, s), 6.95 (1H, d), 7.30 (2H, d), 7.60(1H, t), 7.77 (1H, d), 7.94 (1H, t), 8.72 (1H, d), 11.66 (1H, br s); IR(solid) 1625, 1607, 1551, 1503, 1436, 1404, 1342, 1290, 1254, 1237,1218, 1161, 1137, MS 394.1 (M+H)⁺

Example 14[2-(3-Methylphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-14):

Prepared in a manner similar to the above described Method E to afford apale yellow solid, mp 249-250° C.; ¹H NMR (DMSO) δ2.06 (3H, s), 2.36(3H, s), 5.31 (1H, s), 7.45 (2H, d), 7.48-7.58 (3H, m), 7.61 (1H, d),7.88 (1H, t), 8.68 (1H, d), 11.66 (1H, br s); IR (solid) 1617, 1587,1558, 1496, 14414, 1387, 1341, 1283, 1221, 1162, 1140; MS 348.1 (M+H)⁺

Example 15[2-(2-Methoxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-15):

Prepared in a manner similar to the above described Method E to afford apale yellow solid, mp 237-239° C.; ¹H NMR (DMSO) δ2.07 (3H, s), 3.71(3H, s), 5.35 (1H, s), 7.12 (1H, t), 7.23 (1H, d), 7.55 (1H, t),7.60-7.67 (3H, m), 7.87 (1H, t), 8.66 (1H, d), 11.20 (1H, br s); IR(solid) 1632, 1606, 1561, 1480, 1430, 1405, 1344, 1292, 1276, 1251,1224; MS 364.1 (M+H)⁺

Example 16[2-(2-Naphthalenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-16):

Prepared in a manner similar to the above described Method E to afford apale yellow solid, mp 267-270° C.; ¹H NMR (DMSO) δ2.05 (3H, s), 5.09(1H, s), 7.57 (1H, t), 7.62-7.75 (4H, m), 7.90 (1H, t), 8.07 (3H, t),8.40 (1H, s), 8.66 (1H, d), 11.28 (1H, br s); IR (solid) 1624, 1606,1550, 1487, 1435, 1407, 1341, 1285, 1216, 1158; MS 384.1 (M+H)⁺

Example 17[2-(2,6-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-17):

Prepared in a manner similar to the above described Method E to afford apale brown solid, mp >300° C.; 1H NMR (DMSO) δ2.11 (3H, s), 5.49 (1H,s), 7.49 (1H, t), 7.59-7.67 (2H, m), 7.76 (2H, d), 7.81 (1H, d), 8.60(1H, d), 10.60 (1H, s); IR (solid) 1618, 1599, 1565, 1533, 1486, 1424,1401, 1361, 1344, 1285, 1246, 1216, 1188, 1172; MS 402.0 (M+H)⁺

Example 18[2-(3,4-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-18):

Prepared in a manner similar to the above described Method E to afford apale yellow solid, mp 268-272° C.; ¹H NMR (DMSO) δ2.11 (3H, s), 5.47(1H, s), 7.56 (1H, t), 7.68-7.72 (2H, m), 7.83 (2H, d), 7.88 (1H, t),8.05 (1H, d), 8.66 (1H, d); IR (solid) 1628, 1607, 1556, 1488, 1436,14412, 1399, 1367, 1341, 1288, 1216, 1166; MS 402.0 (M+H)⁺

Example 19[2-(Benzimidazol-2-ylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-19):

Prepared in a manner similar to the above described Method E to afford apale grey solid, mp 192-196° C.; ¹H NMR (DMSO) δ1.60 (3H, s), 5.48 (1H,s), 7.44 (2H, m), 7.53 (1H, t), 7.69 (2H, d), 7.76 (2H, m), 7.85 (1H,t), 8.64 (1H, d), 10.79 (1H, s); IR (solid) 1618, 1606, 1569, 1537,1487, 1411, 1395, 1369, 1343, 1288, 1273, 1170; MS 374.1 (M+H)⁺

Example 20[2-(2-Aminophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-20):

Prepared in a manner similar to the above described Method E to afford abright yellow solid, mp 257-259° C.; ¹H NMR (DMSO) δ2.11-2.30 (3H, 2×brs), 6.10 (1H, br s), 7.10-7.80 (7H, m), 8.60 (1H, br s), 9.80 (1H, brs), 10.80 (1H, br s); IR (solid) 1623, 1591, 1567, 1538, 1496, 1483,1410, 1351

Example 21(5-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenylsulfanyl-quinazolin-4-yl)-amine(IIa-21):

Prepared in a manner similar to the above described Method E to afford ayellow solid, mp 233-236° C.; ¹H NMR (DMSO) δ0.89 (2H, d), 0.98 (2H, d),1.67 (1H, m), 5.48 (1H, s), 7.54-7.73 (7H, m), 7.89 (1H, t), 8.68 (1H,d), 11.60 (1H, br S); IR (solid) 1629, 1606, 1577, 1546, 1509, 1484,1438, 1413, 1370, 1291, 1219; MS 360.3 (M+H)⁺

Example 22(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-amine(IIa-22):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 224-225° C.; ¹H NMR (DMSO) δ0.52 (2H, m), 0.86 (2H, m),1.67 (1H, m), 3.86 (3H, s), 5.60 (1H, s), 7.45 (1H, t), 7.56 (1H, d),7.66 (1H, t), 7.76 (1H, t), 7.93 (1H, d), 8.10 (1H, d), 8.18 (1H, s),8.57 (1H, d), 10.48 (1H, br s), 12.07 (1H, br s); IR (solid) 1724, 1617,1593, 1567, 1526, 1478, 1432, 1400, 1361, 1343, 1283, 1260, 1218, 1169,1128; MS 418.3 (M+H)⁺

Example 23(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methylphenylsulfanyl)-quinazolin-4-yl]-amine(IIa-23):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 241-243° C.; ¹H NMR (DMSO) δ0.55-0.63 (2H, m), 1.87-1.97(1H, m), 1.67-1.79 (1H, m), 2.35 (3H, s), 5.72 (1H, s), 7.30-7.60 (6H,m), 7.68-7.78 (1H,m), 8.50-8.60 (1H, d), 10.38 (1H, s), 12.02 (1H, s);IR (solid) 1617, 1594, 1568, 1529, 1480, 1401, 1344, 1287, 1176, 758,665,656; MS (M+H)⁺

Example 24(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxyphenylsulfanyl)-quinazolin-4-yl]-amine(IIa-24):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 232-234° C.; ¹H NMR (DMSO) δ0.55-0.62 (2H, m), 0.88-0.97(2H, m), 1.70-1.80 (1H, m), 3.79 (3H, s), 5.79 (1H, s), 7.08 (1H, d),7.22-7.29 (2H, m), 7.40-7.50 (2H, m), 7.60 (1H, d), 7.79 (1H, t), 8.57(1H, d), 10.40 (1H, s), 12.04 (1H, s); IR (solid) 3100, 1618, 1592,1567, 1527, 1477, 1402, 1345, 1284, 1246, 1231, 1171, 1041, 1001, 969,826, 761, 692, 667; MS (M+H)⁺

Example 25(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dimethoxyphenylsulfanyl)-quinazolin-4-yl]-amine(IIa-25):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 250-252° C.; ¹H NMR (DMSO) δ0.54-0.60 (2H, m), 0.83-0.91(2H, m), 1.68-1.77 (1H, m), 3.79 (3H, s), 3.85 (3H, s), 5.79 (1H, s),7.10 (1H, d), 7.20-7.26 (2H, m), 7.45 (1H, t), 7.57 (1H, d), 7.77 (1H,t), 8.55 (1H, d), 10.45 (1H, s), 12.04 (1H, m); IR (solid) 1617, 1593,1567, 1530, 1504, 1479, 1457, 1439, 1398, 1364, 1347, 1288, 1269, 1250,1232, 1181, 1169, 1138, 1037, 1020, 997, 972, 882, 846, 804, 764, 750;MS (M+H)⁺

Example 26[2-(3-Carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIa-26):

Prepared from IIa-22 according to Method G to afford a yellow solid,mp >300° C.; ¹H NMR (DMSO) δ0.53 (2H, d), 0.86 (2H, d), 1.65 (1H, m),5.37 (1H, s), 7.55 (1H, t), 7.68 (1H, t), 7.81 (1H, d), 7.88 (1H, t),7.95 (1H, d), 8.15 (1H, d), 8.15 (1H, s), 8.71 (1H, d), 11.32 (1H, brs); IR (solid) 1702, 1626, 1609, 1559, 1490, 1412, 1355, 1293, 1222,1170; MS 404.7(M+H)⁺

Example 27(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphtalen-2-ylsulfanyl)-quinazolin-4-yl]-amine(IIa-27):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 285-288° C.; ¹H NMR (DMSO) δ0.25 (2H, br s), 0.52(2H, br s), 0.87 (1H, m), 5.54 (1H, br s), 7.42-7.77 (4H, m), 8.00 (3H,m), 8.30 (1H, br s), 8.56 (1H, br d), 10.42 and 11.88 (1H, 2×br s); IR(solid) 1615, 1592, 1562, 1527, 1476, 1398, 1366, 1287, 1240, 1216,1167, 1158, 1142, 1128, 996, 965; MS 410.7 (M+H)⁺

Example 28(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,4-difluorophenylsulfanyl)-quinazolin-4-yl]-amine(IIa-28):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 250-253° C.; ¹H NMR (DMSO) δ0.61 (2H, m), 0.91(2H, m), 1.74 (1H, m), 5.67 (1H, m), 7.24-7.28 (1H, m), 7.44-7.48 (3H,m), 7.53-7.81 (2H, brm), 8.55 (1H, m), 10.47 and 12.10 (1H, 2×br s); IR(solid) 1614, 1598, 1565, 1525, 1479, 1423, 1398, 1366, 1345, 1285,1267, 1243, 1213, 1168, 1143, 1114, 1026, 995, 968; MS 396.6(M+H)⁺

Example 29(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-ylsulfanyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine(IIa-29):

Prepared in a manner similar to the above described Method F to afford awhite solid, mp 244° C.; ¹H NMR (DMSO) δ0.13 (2H,s), 0.45 (2H,s), 0.79(1H, s), 1.73 (4H, s), 2.42 (2H, s), 2.58 (2H, s), 5.28 (1H, s), 7.58(2H, d), 7.61 (2H, d), 7.97 (3H, d), 8.23 (1H, s), 8.56 (1H, s), 11.63(1H, s); IR (solid) 1594, 1561, 1514, 1477, 1423, 1333, 1279, 1251, 990,808, 744, 657, 651; MS 414.7(M+H)⁺

Example 30(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,3-dichlorophenylsulfanyl)-quinazolin-4-yl]-amine(IIa-30):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 250-252° C.; ¹H NMR (DMSO) δ0.60 (2H, d), 0.93(2H, d), 1.70 (1H, m), 5.54 (1H, s), 7.47 (2H, m), 7.57 (1H, d), 7.76(1H, t), 7.86 (2H, d), 8.57 (1H, d), 10.48 (1H, s), 12.04 (1H, s); IR(solid) 1616, 1601, 1570, 1528, 1486, 1432, 1400, 1367, 1335, 1285,1246, 1210, 1159, 1146, 1051, 1033, 1021, 997; MS 428.6(M+H)⁺

Example 31[2-(3-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIa-31):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 235-238° C.; ¹H NMR (DMSO) δ0.58 (2H, d), 0.92(2H, d), 1.75 (1H, m), 5.71 (1H, s), 7.44 (1H, t), 7.50-7.63 (4H, m),7.73 (1H, s), 7.75 (1H, t), 8.57 (1H, d), 10.46 (1H, s), 12.08 (1H, s);IR (solid) 1616, 1593, 1562, 1528, 1479, 1456, 1406, 1367, 1343, 1286,1244, 1216, 1176, 1067, 1051, 997; MS 394.7(M+H)⁺

Example 32[2-(2-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIa-32):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 255-257° C.; 1H NMR (DMSO) δ0.59 (2H, d), 0.91(2H, d), 1.71 (1H, m), 5.62 (1H, s), 7.45 (2H, m), 7.57 (1H, m), 7.69(1H, d), 7.75 (1H, t), 7.85 (1H, d), 8.56 (1H, d), 10.43 (1H, s), 12.03(1H, s); IR (solid) 1619, 1596, 1564, 1529, 1480, 1446, 1398, 1370,1343, 1289, 1246, 1218, 1165, 1148, 1089, 1054, 1030, 997; MS394.7(M+H)⁺

Example 33(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dimethylphenylsulfanyl)-quinazolin-4-yl]-amine(IIa-33):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 255-256° C.; ¹H NMR (DMSO) δ0.56 (2H, m), 0.90(2H, m), 1.67 (1H, m), 2.26 and 2.29 (6H, 2×s), 5.75 (1H, br s), 7.26(1H, m), 7.35-7.55 (4H, m), 7.74 (1H, m), 8.54 (1H, br s), 10.44 and12.06 (2H, 2×br s); IR (solid) 1617, 1596, 1569, 1526, 1479, 1459, 1404,1366, 1343, 1287, 1243. 1218, 1167, 1145, 1017, 996, 966; MS 388.3(M+H)⁺

Example 34[2-(Benzimidazol-2-ylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIa-34):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 201-203° C.; ¹H NMR (DMSO) δ0.44 (2H, m), 0.71(2H, m), 1.17 (1H, m), 5.72 (1H, m), 7.23 (2H, m), 7.51-7.81 (5H, m),8.59 (1H, m), 10.59, 12.06 and 13.17 (3H, 3×br s); IR (solid) 1617,1601, 1572, 1532, 1485, 1402, 1374, 1341, 1290, 1273, 1209, 1168, 1024,1010, 965; MS 400.2(M+H)⁺

Example 35(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-amine(IIa-35):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 245-246° C.; ¹H NMR (DMSO) δ0.47 (2H, br s), 0.80(2H, br s), 1.62 (1H, m), 3.85 (3H, s), 5.69 (1H, br s), 7.46 (1H, m),7.58 (1H, m), 7.76-7.81 (3H, m), 8.02-8.05 (2H, m), 8.57 (1H, m), 10.48and 12.11 (2H, 2×br s); IR (solid) 1721, 1712, 1616, 1596, 1572, 1564,1523, 1481, 1435, 1404, 1360, 1346, 1277, 1181, 1114, 1106, 996, 971; MS418.2(M+H)⁺

Example 36[2-(4-Acetamido-phenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIa-36):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 239-241° C.; ¹H NMR (DMSO) δ0.57 (2H, m), 0.83(2H, m), 1.69 (1H, m), 2.02 (3H, s), 5.73 (1H, br s), 7.41 (1H, m),7.53-7.57 (3H, m), 7.73-7.75 (3H, m), 8.54 (1H, m), 10.18, 10.39 and11.98 (3H, 3×br s); IR (solid) 1665, 1618, 1607, 1586, 1572, 1564, 1529,1482, 1387, 1343, 1320, 1287, 1243, 1221, 1162, 1005, 968; MS417.2(M+H)⁺

Example 37(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-l-ylsulfanyl)-quinazolin-4-yl]-amine(IIa-37):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 271-273° C.; ¹H NMR (DMSO) δ0.46-0.47 (2H, m),0.87-0.89 (2H, m), 1.57 (1H, m), 5.01 (1H, m), 7.42 (1H, m), 7.52-7.54(3H, m), 7.64 (1H, m), 7.75 (1H, m), 7.98 (1H, m), 8.06 (1H, m), 8.17(1H, m), 8.28 (1H, m), 8.50 (1H, m), 10.29 (1H, br s), 11.84 (1H, br s);IR (solid) 1615, 1592, 1567, 1528, 1483, 1401, 1362, 1343, 1285, 1242,1219, 1173, 998, 963; MS 410.2(M+H)⁺

Example 38[2-(4-Acetamidophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-38):

Prepared in a manner similar to the above described Method E to affordan white solid, mp 268-271° C.; ¹H NMR (DMSO) δ2.02 (3H, s), 2.09 (3H,s), 5.56 (1H, s), 7.40 (1H, t), 7.55 (3H, m), 7.75 (3H, d), 8.55 (1H,d), 10.21 (1H, s), 10.40 (1H, s), 12.03 (1H, s); IR (solid) 1662, 1620,1599, 1572, 1531, 1438, 1397, 1370, 1358, 1341, 1323, 1312, 1278, 1265,1245, 1216, 1161, 1006, 966; MS 391.2(M+H)⁺

Example 39[2-(4-Methanesulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-39):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 219-222° C.; ¹H NMR (DMSO) δ2.15 (3H, s), 2.61(3H, s), 5.84 (1H, s), 6.91 (2H, d), 7.22 (2H, d), 7.36 (1H, s), 7.52(1H, d), 7.69 (1H, s), 8.53 (1H, d), 10.31 (1H, s), 11.96 (1H, S); IR(solid) 1621, 1602, 1584, 1567, 1528, 1486, 1351, 1287, 1253, 1207,1179, 1102, 1091, 983; MS 427.0(M+H)⁺

Example 40[2-(4-Acetamidophenylsulfanyl)-7-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-40):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 291-293° C.; ¹H NMR (DMSO) δ2.01 (3H, s), 2.09 (3H, s),3.87 (3H, s), 5.55 (1H, s), 6.96 (1H, s), 6.99 (1H, d), 7.55 (2H, d),7.73 (2H, d), 8.45 (1H, d), 10.21 (1H, s), 10.23 (1H, s), 11.99 (1H, s);IR (solid); MS 421.2(M+H)⁺

Example 41[2-(4-Acetamidophenylsulfanyl)-8-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-41):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 262-264° C.; ¹H NMR (DMSO) δ1.94 (2H, quint.), 2.03 (3H,s), 2.09 (3H, s), 2.38 (4H, s), 2.45 (2H, t), 3.58 (4H, s), 4.11 (2H,t), 5.60 (1H, s), 7.24 (1H, d), 7.30 (1H, t), 7.57 (2H, d), 7.73 (2H,d), 8.07 (1H, d), 10.20 (1H, s), 10.24 (1H, s), 12.02 (1H, br s); IR(solid) 3245, 3045, 2954, 2918, 2845, 1663, 1609, 1586, 1527, 1468,1391, 1332, 1268, 1254, 1159, 1136, 1114, 1054, 995, 823 ; MS534.4(M+H)⁺

Example 42[2-(4-Methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-42):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 257-260° C.; ¹H NMR (DMSO) δ1.95 (3H, s), 3.89(3H, s), 5.51 (1H, br s), 7.39 (1H, br s), 7.51 (1H, br s), 7.70 (1H, brs), 7.81 (2H, d), 8.04 (2H, d), 8.51 (1H, br s), 10.48 (1H, br s), 12.03(1H, br s); IR (solid) 1718, 1618, 1599, 1568, 1531, 1481, 1434, 1395,1362, 1342, 1286, 1247, 1216, 1156, 1116, 1018, 1003, 968 ; MS392.2(M+H)⁺

Example 43[2-(4-Carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-43):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 263-265° C.; ¹H NMR (DMSO) δ1.98 (3H, s), 5.50(1H, s), 7.46 (1H, t), 7.60 (1H, d), 7.78 (3H, m), 8.02 (2H, d), 8.58(1H, d), 10.58 (1H, s), 12.50 (1H, br s); IR (solid) 1623, 1605, 1574,1560, 1533, 1490, 1401, 1349, 1318, 1285, 1249, 1216, 1174, 1131, 1088,1018; MS 378.2(M+H)⁺

Example 44[2-(4-Acetamidophenylsulfanyl)-8-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-44):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 247-249° C.; ¹H NMR (DMSO) 1.99 (3H, s), 2.10(3H, s), 3.93 (3H, s), 5.40 (1H, s), 7.31 (1H, d), 7.38 (1H, t), 7.57(2H, d), 7.76 (2H, d), 8.11 (1H, d), 10.28 (1H, s), 10.61 (1H, s), 12.11(1H, br s); IR (solid) 3234, 3052, 2938, 1673, 1618, 1591, 1536, 1481,1459, 1390, 1372, 1345, 1317, 1267, 1249, 1158, 1058, 985, 830; MS421.2(M+H)⁺

Example 45[2-(4-Acetamidophenylsulfanyl)-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-45):

Prepared from IIa-74 according to Method I to afford an off-white solid,mp 153° C. (dec.); ¹H NMR (DMSO) δ2.02 (3H, s), 2.09 (3H, s), 2.29 (2H,quint.), 3.16 (2H, m), 3.36 (4H,m), 3.57 (4H, m), 4.11 (2H, m), 5.58(1H, s), 7.22-7.29 (2H, m), 7.55 (2H, d), 7.76 (2H, d), 8.07 (1H, d),10.26 (1H, br s), 10.35 (1H, s), 12.06 (1H, br s); IR (solid) 1673,1614, 1591, 1532, 1486, 1391, 1336, 1254, 1109, 1063, 995; MS534.2(M+H)⁺

Example 46[2-(4-Bromophenylsulfanyl)quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-46):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp >300° C.; ¹H NMR (DMSO) δ2.15 (3H, s), 5.63 (1H,br s), 7.44 (1H, m), 7.55-7.62 (3H, m), 7.69-7.77 (3H, m), 8.56 (1H, m),10.47 and 12.12 (2H, 2×br s); IR (solid) 1615, 1597, 1565, 1525, 1478,1396, 1362, 1339, 1285, 1218, 1158, 1034, 1009, 967; MS412.1/414.1(M+H)⁺

Example 47[2-(3-Bromophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-47):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 280-281° C.; ¹H NMR (DMSO) δ2.12 (3H, s), 5.54(1H, br s), 7.46 (1H, m), 7.55-7.68 (3H, m), 7.75-7.88 (3H, m), 8.81(1H, m), 10.49 and 12.11 (2H, 2×br s); IR (solid) 1617, 1600, 1567,1530, 1483, 1399, 1362, 1342, 1282, 1200, 1168, 1054, 1034, 1005, 967;MS 412.2/414.2(M+H)⁺

Example 48[2-(4-Isopropanesulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-48):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 294-297° C.; ¹H NMR (DMSO) δ1.26 (6H, d), 2.13 (3H, s),5.75 (1H, s), 7.34 (2H, d), 7.41 (1H, t), 7.54 (1H, d), 7.59 (2H, d),7.73 (1H, t), 8.53 (1H, d), 10.16 (1H, s), 10.42 (1H, s), 12.07 (1H, brs); IR (solid) 1613, 1593, 1560, 1530, 1482, 1384, 1364, 1346, 1320,1290, 1265, 1243, 1216, 1169, 1141, 1084, 1056, 1019, 999, 969, 916; MS455.2(M+H)⁺

Example 49[2-(4-Isobutyrylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-49):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 285-287° C.; ¹H NMR (DMSO) δ1.12-1.13 (6H, m),1.99 (3H, s), 2.64 (1H, m), 5.52 (1H, br s), 7.41 (1H, m), 7.54-7.57(3H, m), 7.72-7.77 (3H, m), 8.54 (1H, m), 10.12, 10.41 and 12.04 (3H,3×br s); IR (solid) 1704, 1680, 1617, 1590, 1566, 1516, 1481, 1395,1358, 1341, 1286, 1247, 1214, 1155, 1052, 1032, 1006, 969; MS419.3(M+H)⁺

Example 50(5-Methyl-2H-pyrazol-3-yl)-[2-(4-propionylamino-phenylsulfanyl)-quinazolin-4-yl]-amine(IIa-50):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 281-282° C.; ¹H NMR (DMSO) δ1.11-1.13 (3H, 2.33(2H, m), 5.51 (1H, br s), 7.41 (1H, m), 7.55-7.57 (3H, m), 7.71-7.78(3H, m), 8.54 (1H, m), 10.11, 10.41 and 12.04 (3H, 3×br s); IR (solid)1654, 1621, 1599, 1571, 1527, 1476, 1398, 1358, 1341, 1286, 1244, 1216,1155, 1006, 969; MS 405.3(M+H)⁺

Example 51[2-(4-cyclopropanecarbonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-51):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 300-303° C.; 1H NMR (DMSO) δ0.82-0.84 (4H, m),1.83 (1H, m), 2.01 (3H, S), 5.55 (1H, br s), 7.39-7.41 (2H, m),7.53-7.57 (2H, m), 7.72-7.77 (2H, m), 8.53-8.55 (2H, m), 10.40, 10.46and 12.03 (3H, 3×br s); IR (solid) 1664, 1614, 1591, 1560, 1526, 1480,1432, 1390, 1344, 1288, 1240, 1194, 1177, 1152, 997; MS 417.2(M+H)⁺

Example 52[2-(4-Acetamido-phenylsulfanyl)-8-hydroxyquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-52):

tan solid, mp 258-259° C.; 1H NMR (DMSO) δ1.99 (3H, s), 2.09 (3H, s),5.45 (1H, s), 7.10 (1H, d), 7.22 (1H, t), 7.57 (2H, d), 7.75 (2H, d),7.95 (1H, d), 9.35 (1H, s), 10.22 (1H, s), 10.26 (1H, s), 12.00 (1H, brs); IR (solid) 3295, 3272, 3181, 3109, 1654, 1591, 1527, 1482, 1459,1386, 1368, 1314, 1268, 1141, 1077, 991, 814; MS 407.2(M+H)⁺

Example 53[2-(4-Acetamido-phenylsulfanyl)-7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-53):

Prepared in a manner similar to the above described Method E to afford ayellow solid; ¹H NMR (DMSO) δ2.02 (3H, s), 2.09 (3H, s), 5.54 (1H, s),7.58 (2H, d), 7.75 (2H, d), 8.08 (1H, d), 8.22 (1H, s), 8.80 (1H, d),10.24 (1H, s), 10.85 (1H, s), 12.15 (1H, s); IR (solid); MS 436.2(M+H)⁺

Example 54(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(propane-1-sulfonylamino)-phenylsulfanyl]-quinazolin-4-yl}-amine(IIa-54):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 272-273° C.; ¹H NMR (DMSO) δ0.95 (3H, t), 1.71 (2H, m),2.13 (3H,s), 3.18 (2H, t), 5.70 (1H, s), 7.31 (2H, d), 7.41 (1H, t),7.52 (1H, d), 7.58 (1H, d), 7.73 (1H, t), 8.55 (1H, d), 10.16 (1H, s),10.42 (1H, s), 12.07 (1H, s); IR (solid) 1615, 1594, 1563, 1530, 1481,1389, 1362, 1346, 1325, 1291, 1245, 1147, 969; MS 455.-2(M+H)⁺

Example 55[2-(4-Ethylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-55):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 279-280° C.; ¹H NMR (DMSO) δ1.28 (3H, t), 2.19(3H,s), 3.25 (2H, m), 5.76 (1H, s), 7.36 (2H, d), 7.48 (1H, t), 7.53(1H, d), 7.65 (1H, d), 7.80 (1H, t), 8.61 (1H, d), 10.23 (1H, s), 10.49(1H, s), 12.13 (1H, s); IR (solid) 1615, 1597, 1564, 1532, 1506, 1485,1455, 1388, 1361, 1347, 1323, 1294, 1218, 1150, 1033, 1016, 998, 968,918; MS 441.2(M+H)⁺

Example 56[2-(4-Acetamido-phenylsulfanyl)-7-hydroxyaminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-56):

Prepared from IIa-53 according to Method J to afford a yellow solid; ¹HNMR (DMSO) δ1.97 (3H, s), 2.11 (3H, s), 5.19 (1H, s), 6.88-6.91 (2H, m),7.65 (2H, d), 7.85 (2H, d), 8.44 (1H, d), 9.27 (1H, br s), 10.49 (1H,s), 11.38 (1H, s), 14.58 (1H, br s); IR (solid); MS 422.2 (M+H)⁺

Example 57[2-(4-Isobutanecarbonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-57):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 281-282° C.; ¹H NMR (DMSO) δ0.95-0.97 (6H, m), 2.00 (3H,s), 2.12 (1H, m), 2.23-2.25 (2H, m), 5.56 (1H, s), 7.41 (1H, m),7.54-7.57 (3H, m), 7.72-7.78 (3H, m), 8.54 (1H, m), 10.14, 10.41 and12.03 (3H, 3×br s); IR (solid) 1737, 1658, 1618, 1599, 1566, 1530, 1483,1432, 1394, 1364, 1343, 1313, 1287, 1242, 1216, 1167, 1151, 1003, 967;MS 433.2(M+H)⁺

Example 58[2-(4-tert-Butoxycarbonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-58):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 243-246° C.; ¹H NMR (DMSO) δ1.50 (9H, s), 1.97 (3H,s),5.40 (1H, s), 7.07 (2H, br s), 7.36 (1H, br s), 7.47 (2H, d), 7.58 (2H,d), 8.12 (1H, br s), 9.58 (1H, s), 11.24 (1H, br s); IR (solid) 1701,1593, 1559, 1515, 1482, 1396, 1365, 1346, 1308, 1288, 1237, 1154, 1051,1020, 969; MS 449.2(M+H)⁺

Example 59[2-(4-Acetamido-phenylsulfanyl)-7-aminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-59):

Prepared from IIa-53 according to Method K to afford an off-white solid,mp 264-265 ° C.; ¹H NMR (DMSO) δ1.99 (3H, s), 2.09 (1H, s), 5.53 (1H,s), 5.97 (2H, s), 6.47 (1H, s), 6.68 (1H, d), 7.52 (2H, d), 7.71 (2H,d), 8.15 (1H, d), 9.83 (1H, br s), 10.19 (1H, s), 10.87 (1H, br s); IR(solid); MS 406.2(M+H)⁺

Example 60(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(2-morpholin-4-yl-acetylamino)-phenylsulfanyl]-quinazolin-4-yl}-amine(IIa-60):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 266-267° C.; ¹H NMR (DMSO) δ2.03 (3H, s), 2.57(4H, m), 3.23 (2H,s), 3.69 (4H, m), 5.58 (1H, s), 7.40 (1H, t),7.55-7.62 (3H, m), 7.75 (1H, t), 7.80 (2H, d ), 8.54 (1H, d), 10.02 (1H,s), 10.41 (1H, S), 12.03 (1H,s); IR (solid) 1686, 1598, 1564, 1533,1515, 1484, 1387, 1362, 1348, 1291, 1113, 868, 801, 773; MS 476.4(M+H)⁺

Example 61(5-Cycloprpyl-2H-pyrazol-3-yl)-[2-(4-methylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-amine(IIa-61):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 235-238° C.; ¹H NMR (DMSO) δ0.61 (2H, s), 0.92 (2H, d),1.82 (1H, br s), 2.98 (3H,s), 5.90 (1H, s), 7.23 (2H, d), 7.41 (1H, t),7.54 (3H, m), 7.72 (1H, t), 8.55 (1H, d), 10.16 (1H, br s), 10.38 (1H,s), 11.99 (1H, s); IR (solid) 1621, 1605, 1573, 1532, 1494, 1455, 1375,1342, 1316, 1290, 1232, 1143, 1113, 985, 972; MS 453.3(M+H)⁺

Example 62[2-(4-Amino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-62):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp >300° C.; ¹H NMR (DMSO) δ2.16 (3H, s), 5.58 (1H,s), 6.78 (2H,. d), 7.36 (2H, d), 7.64 (2H, m), 7.94 (1H, t), 8.74 (1H,d), 11.82 (1H, br s); IR (solid) 1615, 1591, 1561, 1532, 1495, 1480,1387, 1363, 1344, 1288, 1244, 1148, 966; MS 349.2(M+H)⁺

Example 63[2-(4-Acetamido-phenylsulfanyl)-quinazolin-4-yl]-(2H-pyrazol-3-yl)-amine(IIa-63):

Prepared in a manner similar to the above described Method E to afford awhite solid, ¹H NMR (DMSO) δ2.11 (3H, s), 5.93 (1H, s), 7.31-7.68 (8H,m), 8.54 (1H, s), 10.17 (1H, s), 10.54 (1H, s), 12.38 (1H, s); IR(solid); MS 377.4(M+H)⁺

Example 64(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(4-morpholin-4-yl-butyrylamino)-phenylsulfanyl]-quinazolin-4-yl}-amine(IIa-64):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 240-243° C.; ¹H NMR (DMSO) δ1.77 (2H, m), 2.00 (3H, s),2.31-2.38 (8H, m), 3.57 (4H, m), 5.54 (1H, s), 7.39-7.76 (7H, m), 8.53(1H, br m), 10.15 (1H, s), 10.41 (1H, s), 12.00 (1H, br s); IR (solid);MS 504.3(M+H)⁺

Example 65(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(2-morpholin-4-yl-ethylcarbamoyl)-phenylsulfanyl]-quinazolin-4-yl}-amine(IIa-65):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 246-248° C.; ¹H NMR (DMSO) δ1.97 (3H, s), 2.43 (4H, brs), 3.30 (2H, s), 3.42 (2H, m), 3.58 (4H, br s), 5.52 (1H, s), 7.43 (1H,t), 7.55 (1H, d), 7.76 (3H, m), 7.97 (2H, d), 8.56 (2H, m), 10.45 (1H,s), 12.05 (1H, br s); IR (solid) 1637, 1618, 1596, 1568, 1530, 1484,1396, 1362, 1343, 1286, 1247, 1216, 1159, 1116, 1006, 967; MS490.3(M+H)⁺

Example 66[8-Methoxy-2-(4-methylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-66):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 275-277° C.; ¹H NMR (DMSO) δ2.10 (3H, s), 3.07(3H, s), 3.89 (3H, s), 5.58 (1H, s), 7.24 (1H, d), 7.26-7.36 (3H, m),7.60 (2H, d), 8.07 (1H, d), 10.13 (1H, s), 11.26 (1H, s), 12.03 (1H, s);IR (solid) 3379, 1622, 1595, 1531, 1481, 1467, 1344, 1326, 1271, 1248,1143, 1061, 993, 975, 924, 829; MS 457.2(M+H)⁺

Example 67{2-[4-(2-Dimethylamino-ethylcarbamoyl)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-67):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 192-193° C.; ¹H NMR (DMSO) δ1.99 (3H, s), 2.20 (6H,s),2.42 (2H, t), 3.40 (2H, q), 5.56 (1H, s), 7.43 (1H, t), 7.57 (1H, d),7.77 (3H, m), 7.92 (2H, d), 8.56 (2H, m), 10.44 (1H, s), 12.04 (1H, brs); IR (solid) 1650, 1618, 1593, 1561, 1525, 1481, 1419, 1395, 1361,1337, 1287, 1247, 1214, 1165, 1004, 969; MS 448.3(M+H)⁺

Example 68{2-[4-(2-Dimethylamino-acetylamino)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-68):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 241-243° C.; ¹H NMR (DMSO) δ2.00 (3H, s), 2.33 (6H, s),3.14 (2H, s), 5.60 (1H, s), 7.40 (1H, t), 7.58 (3H, m ), 7.77 (1H, t ),7.76 (2H, d), 8.58 (1H, d), 10.04 (1H, s), 10.42 (1H, s), 11.99 (1H,s).; IR (solid) 1707, 1617, 1601, 1571, 1509, 1485, 1420, 1397, 1365,1304, 1290, 1243, 1215, 1161, 970, 847, 813, 765, 716, 683, 656; MS434.3(M+H)⁺

Example 69[8-Hydroxy-2-(4-methylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-69):

pale green solid, mp 291-293° C.; ¹H NMR (DMSO) δ2.10 (3H, s), 3.09 (3H,s), 5.57 (1H, s), 7.11 (1H, d), 7.24 (1H, t), 7.31 (2H, d), 7.62 (2H,d), 7.96 (1H, d), 9.32 (1H, s), 10.16 (1H, s), 11.28 (1H, s), 12.02 (1H,s); IR (solid) 3256, 1596, 1531, 1460, 1392, 1317, 1334, 1296, 1267,1146, 993, 968, 931, 824; MS 443.2(M+H)⁺

Example 70{2-[4-(3-Dimethylamino-propylcarbamoyl)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-70):

Prepared in a manner similar to the above described Method E to afford apink solid, mp 210-213° C.; ¹H NMR (DMSO) δ1.48 (2H, m), 2.01 (3H, s),2.24 (6H,s), 2.38 (2H, br s), 2.93 (2H, s), 5.57 (1H, s), 7.48 (1H, t),7.62 (1H, d), 7.80 (3H, m), 8.02 (2H, d), 8.61 (1H, d) 8.74 (1H, s),10.50 (1H, s), 12.15 (1H, br s); IR (solid) 1682, 1618, 1595, 1567,1528, 1484, 1400, 1361, 1344, 1285, 1247, 1219, 1172, 1084, 1006, 969;MS 462.3(M+H)⁺

Example 71{2-[4-(3-Dimethylamino-propionylamino)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-71):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 280° C. (dec.); ¹H NMR (DMSO) δ2.09 (3H, s), 2.60(6H, s), 2.93 (2H, m), 3.10 (2H, m), 5.64 (1H, s), 7.47 (1H, t),7.59-7.70 (3H, m), 7.80-7.87 (3H, m), 8.61 (1H, d), 10.47 (1H, s), 10.48(1H, S), 12.15 (1H, s).; IR (solid) 1670, 1619, 1598, 1586, 1571, 1534,1515, 1481, 1397, 1364, 1348, 1286, 1178, 1162, 764; MS 448.4(M+H)⁺

Example 72[2-(4-Acetamido-phenylsulfanyl)-8-methoxy-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIa-72):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 265-268° C.; ¹H NMR (DMSO) δ0.49-0.56 (2H, m),0.79-0.83 (2H, m), 1.55-1.70 (1H, m), 2.06 (3H, s), 3.89 (3H, s), 5.61(1H, s), 7.25 (1H, d), 7.33 (1H, t), 7.56 (2H, d), 7.74 (2H, d), 8.07(1H, d), 10.17 (1H, s), 10.26 (1H, s), 11.94 (1H, br s); IR (solid)3250, 1671, 1617, 1595, 1536, 1480, 1460, 1396, 1373, 1335, 1254, 1160,1131, 1071, 1011, 984, 869, 815; MS 447.4(M+H)⁺

Example 73[2-(4-Acetamidophenylsulfanyl)-8-(3-dimethylamino-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-73):

Prepared in a manner similar to the above described Method E to affordan off-white solid, mp 170-172° C.; ¹H NMR (DMSO) δ1.91 (2H, quint.),2.03 (3H, s), 2.09 (3H, s), 2.17 (6H, s), 2.40 (2H, t), 4.10 (2H, t),5.59 (1H, s), 7.23 (1H, d), 7.30 (1H, t), 7.57 (2H, d), 7.73 (2H, d),8.06 (1H, d), 10.20 (1H, s), 10.24 (1H, s), 12.02 (1H, br s); IR (solid)3234, 3108, 1675, 1614, 1592, 1531, 1484, 1395, 1371, 1338, 1316, 1253,1161, 1137, 1062, 1038, 994, 958, 823; MS 492.4(M+H)⁺

Example 74[2-(4-Acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-74):

Prepared from IIa-40 according to Method H to afford an off-white solid,mp 246-248° C.; ¹H NMR (DMSO) δ2.00 (3H, s), 2.08 (3H, s), 5.52 (1H, s),6.78 (1H, s), 6.87 (1H, d), 7.54 (2H, d), 7.72 (2H, d), 8.37 (1H, d),10.06 (1H, s), 10.17 (1H, s), 10.37 (1H, s), 11.95 (1H, br s); IR(solid) 1661, 1633, 1594, 1572, 1539, 1492, 1420, 1389, 1359, 1298,1223, 1176, 1148, 1087, 1026, 1010, 965; MS 407.4(M+H)⁺

Example 75[2-(4-Acetamidophenylsulfanyl)-7-(3-dimethylamino-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-75):

Prepared in a manner similar to the above described Method I to affordan off-white solid, mp 249-250° C.; ¹H NMR (DMSO) δ1.90 (2H, quint.),2.01 (3H, s), 2.09 (3H, s), 2.19 (6H, s), 2.42 (2H, m), 4.12 (2H, t),5.55 (1H, s), 6.93 (1H, s), 6.98 (1H, d), 7.55 (2H, d), 7.73 (2H, d),8.43 (1H, d), 10.21 (1H, s), 10.23 (1H, s), 11.98 (1H, br s); IR (solid)3272, 1677, 1615, 1571, 1558, 1530, 1501, 1434, 1420, 1394, 1344, 1320,1292, 1263, 1222, 1168, 1048, 1034, 1005, 967, 864, 844; MS 492.4(M+H)⁺

Example 76(2-{4-[2-(tert-Butoxycarbonyl-methyl-amino)-acetylamino]-phenylsulfanyl}-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-76):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 228-229° C. (dec.); ¹H NMR (DMSO) δ1.37 (3H, s), 1.40(3H, s), 2.02+2.03 (3H, 2×s), 2.88+2.90 (3H, 2×s), 4.01+4.02 (2H, 2×s),5.52+5.57 (1H, 2×s), 7.47 (1H, t), 7.55-7.63 (3H, m), 7.75-7.80 (3H, m),8.60 (1H,d), 10.28+10.30 (1H, 2×s), 10.45 (1H, s), 12.08 (1H, s).; IR(solid) 1698, 1683, 1653, 1617, 1594, 1559, 1538, 1532, 1507, 1488,1457, 1418, 1397, 1364, 1346, 1307, 1287, 1246, 1151, 842, 827, 759; MS520.4 (M+H)⁺

Example 77{2-[4-(2-Methylamino-acetylamino)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-77):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 242-244° C.; ¹H NMR (DMSO) δ2.01 (3H, s), 2.34 (3H, s),3.32 (2H, s), 5.58 (1H, s), 7.45 (1H, t), 7.50-7.60 (3H, m), 7.75 (1H,t), 7.80 (2H, d), 8.55 (1H, d), 10.10 (1H, br s), 10.42 (1H, s), 12.02(1H, s); IR (solid) 1674, 1619, 1598, 1570, 1525, 1483, 1417, 1363,1345, 1298, 1285, 1247, 1160, 966, 827, 804, 784, 763, 712, 670, 653; MS420.4 (M+H)⁺

Example 78[2-(4-Acetamidophenylsulfanyl)-8-fluoro-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-78):

Prepared in a manner similar to the above described Method E to afford awhite solid, mp 257-259° C.; ¹H NMR (DMSO) δ2.01 (3H, s), 2.09 (3H, s),5.49 (1H, s), 7.42 (1H, t), 7.57-7.68 (3H, m), 7.75 (2H, d), 8.40 (1H,d), 10.28 (1H, s), 10.75 (1H, s); ¹⁹F NMR (DMSO) δ-127.3; IR (solid)1690, 1670, 1637, 1609, 1588, 1543, 1519, 1493, 1456, 1434, 1395, 1366,1332, 1315, 1289, 1254, 1242, 1032, 838, 829, 808, 744; MS 409.4(M+H)⁺

Example 79 (1H-Indazol-3-yl)-(2-phenylsulfanyl-quinazolin-4-yl)-amine(IIa-79):

Prepared in a manner similar to the above described Method E to afford awhite solid. ¹H NMR (DMSO) δ7.07 (m, 3H), 7.19 (t, 1H), 7.37 (d, 2H),7.39 (t, 1H), 7.52 (dd, 1H), 7.54 (t, 1H), 7.55 (d, 1H), 7.56 (t, 1H),7.83 (t, 1H), 8.53 (d, 1H), 10.71 (s, 1H), 12.85 (s, 1H); MS 370.1(M+H)⁺

Example 80{2-[(2-Hydroxyethyl)phenylamino]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-1):

Prepared in a manner similar to the above described Method A to afford abrown solid, mp 217° C.; ¹H NMR (DMSO) δ1.99 (3H, s), 3.69 (2H, t), 4.05(2H, t), 5.00 (1H, br s), 5.53 (1H, br s), 7.09 (1H, m), 7.25-7.40 (4H,m), 7.40-7.48 (2H, m), 7.54 (1H, m), 8.34 (1H, m), 10.07 (1H, s), 11.67(1H, br s); IR (solid) 3395, 3155, 3052, 2934, 1623, 1598, 1577, 1475,1434, 1393; MS 361.2 (M+H)⁺

Example 81[2-(Methylphenylamino)-guinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-2):

Prepared in a manner similar to the above described Method A to afford awhite solid, mp 154-156° C.; ¹H NMR (DMSO) δ2.03(3H, s), 3.51(3H, s),5.70(1H, s), 7.13(1H, m), 7.36-7.25(3H, m), 7.48-7.37 (3H, m), 7.58 (1H,m), 8.38 (1H, d), 9.98(1H, s), 11.91 (1H s); IR (solid) 1621, 1598,1578, 1540, 1494, 1473, 1398, 1374; MS 331.0 (M+H)⁺

Example 82(5-methyl-2H-pyrazol-3-yl)-{2-[N-methyl-N-(pyridin-3-ylmethyl)amino]-quinazolin-4-yl}-amine(IIc-3):

Prepared in a manner similar to the above described Method A to afford ayellow solid, mp 177° C.; ¹H NMR(DMSO) δ0.45 (2H, s), 0.84 (2H, s), 1.80(1H, s), 3.16 (3H, s), 4.93 (2H, s), 6.18 (1H, br s), 7.10 (1H, t), 7.34(2H, s), 7.55 (1H, t), 7.64 (1H, s), 8.36 (1H, d), 8.45 (1H, s), 8.52(1H, s), 10.03 (1H, s), 12.17 (1H, s); IR (solid) 3104, 2995, 2936,1618, 1591, 1559, 1541, 1518, 1477, 1409, 1386, 1350, 1300, 1018, 991,873, 827; MS 372.3 (M+H)⁺

Example 83(5-Methyl-2H-pyrazol-3-yl)-(2-phenylamino-quinazolin-4-yl)-amine(IIc-4):

Prepared in a manner similar to the above described Method A to afford awhite solid; ¹H NMR (DMSO @60° C.) δ2.27(3H, s), 6.47(1H, br s),6.92(1H, m), 7.31(3H, m), 7.53(1H, m), 7.70 (1H, m), 7.91 (2H, m), 8.37(2H, d), 9.16 (1H, br s), 10.05 (1H, br s), 12.15 (1H, br s); IR (solid)1623, 1601, 1573, 1541, 1478; MS 317.0 (M+H)⁺

Example 84(2-Benzylamino-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-5):

Prepared in a manner similar to the above described Method A to afford awhite solid, mp 225-227° C.; ¹H NMR (DMSO) δ2.20 (3H, s), 4.62(2H, d),7.18 (1H, s), 7.43-7.60(8H, m), 8.22 (1H, s), 9.99 (1H, br s), 12.05(1H, br s); IR (solid) 1630, 1609, 1578, 1538, 1511; MS 331.0 (M+H)⁺

Example 85(2-Cyclohexylamino-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-6):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 280° C. (dec.); 1H NMR (DMSO) δ1.11-1.44(5H, m),1.56 (1H, m), 1.71(2H, m), 1.92 (2H, m), 2.26(3H, s), 3.75(1H, s), 6.63(1H, br s), 7.04 (1H, s), 7.28 (1H, s), 7.51(1H, m), 8.26(1H, s),9.97(1H, br s), 12.08(1H, br s), 12.75(1H, br s); IR (solid) 2927, 2853,1619, 1596, 1569, 1522, 1482; MS 323.0 (M+H)⁺

Example 86[2-(2,3-Dihydrobenzo[1,4]dioxin-6-ylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-7):

Prepared in a manner similar to the above described Method A to affordan off-green solid, mp >250° C.; ¹H NMR (DMSO) δ2.23 (3H, s), 4.15 (4H,m), 6.32 (1H, br s), 6.76 (1H, d), 7.16 (1H, t), 7.22 (1H, dd), 7.39(1H, d), 7.57 (1H, t), 7.66 (1H, s), 8.34 (1H, d), 9.07 (1H, br s),10.20 (1H, br s), 12.15 (1H, br s); IR (solid) 3445, 3045, 2968, 2927,2868, 1618, 1595, 1577, 1559, 1509, 1441, 1377, 1073; MS 375.1 (M+H)⁺

Example 87(2-Cyclohexylmethylamino-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-8):

Prepared in a manner similar to the above described Method A to afford awhite solid, mp 211° C.; ¹H NMR (DMSO) δ0.85-1.30 (5H, m), 1.50-1.85(6H, m), 2.22 (3H, s), 3.19 (2H, s), 6.50-7.00 (1H, br s), 7.06 (1H, brs), 7.29 (1H, br s), 7.51 (1H, t), 8.26 (1H, br s), 9.97 (1H, br s),12.04 (1H, br s), 12.75 (1H, br s); IR (solid) 3333, 2927, 2850, 2831,1627, 1609, 1577, 1540, 1508, 1449, 1422, 1340, 988; MS 337.4 (M+H)⁺

Example 88[2-(1H-Indazol-6-ylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-9):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp >250° C.; ¹H NMR (DMSO) δ2.24 (3H, s), 5.93 and6.89 (1H, 2×br s), 7.05-8.15 (6H, m), 8.25-8.90 (2H, m), 9.25 and 9.97(1H, 2×br s), 10.11 and 10.57 (1H, 2×br s), 12.15 and 12.80 (2H, 2×brs); IR (solid) 3456, 3315, 2923, 1613, 1600, 1577, 1549, 1467; MS 357.1(M+H)⁺

Example 89(5-Methyl-2H-pyrazol-3-yl)-[2-(pyridin-3-ylmethylamino)-quinazolin-4-yl]-amine(IIc-10):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 218° C.; ¹H NMR (DMSO) δ2.20 (3H, s), 4.59 (2H,s), 6.30 (1H, br s), 7.10 (1H, s), 7.33 (2H, s), 7.54 (1H, s), 7.78 (1H,s), 8.31 (1H, s), 8.43 (1H, s), 8.61 (1H, s), 10.0 (1H, br s), 12.15(1H, br s); IR (solid) 3308, 2945, 2919, 2858, 1623, 1593, 1577, 1552,1501, 1475, 1449, 1383; MS 332.1-(M+H)⁺

Example 90[2-(3-Chlorophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-11):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp >250° C., ¹H NMR (DMSO) δ2.29 (3H, s), 5.30-6.98(1H, m), 6.96 (1H, s), 7.28 (2H, s), 7.51 (1H, s), 7.67 (1H, s), 7.77(1H, s), 8.23 (1H, s), 8.46 (1H, s), 9.35 and 10.00 (1H, 2×br s), 10.14and 10.64 (1H, 2×br s), 12.20 and 12.82 (1H, 2×br s); IR (solid) 3447,3078, 2945, 2914, 2863, 1618, 1600, 1572, 1549, 1472, 1440, 1403, 1372;MS 351.1 (M+H)⁺

Example 91[2-(4-Chlorophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-12):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp >250° C.; ¹H NMR (DMSO) δ2.27 (3H, s), 5.20-6.80(1H, m), 7.26 (1H, s), 7.33 (2H, s), 7.51 (1H, s), 7.66 (1H, s), 7.99(2H, d), 8.42 (1H, s), 9.29 and 9.93 (1H, 2×br s), 10.13 and 10.55 (1H,2×br s), 12.19 and 12.81 (1H, 2×br s); IR (solid) 3439, 3057, 2957,1618, 1600, 1586, 1572, 1550, 1504, 1486, 1431, 1413, 1367; MS 351.1(M+H)⁺

Example 92[2-(4-Fluorobenzylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-13):

Prepared in a manner similar to the above described Method A to afford awhite solid, mp 216° C.; ¹H NMR (DMSO) δ2.20 (3H, s), 4.56 (2H, d), 6.30(1H, br s), 7.05-7.20 (3H, m), 7.31 (1H, d), 7.42 (2H, S), 7.54 (1H, t),8.32 (1H, s), 10.01 and 10.34 (1H, 2×br s), 12.09 and 12.75 (1H, 2×brs); IR (solid) 3333, 2854, 1632, 1609, 1577, 1536, 1508, 1367; MS 349.3(M+H)⁺

Example 93{2-[2-(2-Hydroxyethyl)phenylamino]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-14):

Prepared in a manner similar to the above described Method A to afford awhite solid, mp 222° C.; ¹H NMR (DMSO) δ2.09 (3H, s), 2.80 (2H, t), 3.61(2H, t), 4.87 (1H, br s), 5.85 (1H, br s), 7.30-7.53 (5H, m), 7.63 (1H,d), 7.86 (1H, t), 8.68 (1H, d), 10.11 (1H, br s), 11.55 (1H, br s),12.49 (1H, br s), 13.50 (1H, br s); IR (solid) 3193, 3171, 3111, 3084,1636, 1577, 1559, 1509, 1486, 1413, 1340, 1058; MS 361.3 (M+H)⁺

Example 94[2-(4-cyanomethylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-15):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp >250° C.; ¹H NMR (DMSO) 2.23 (3H, s), 4.09 (2H,s), 6.28 (1H, br s), 7.41 (2H, d), 7.48 (1H, t), 7.57-7.63 (3H, m), 7.87(1H, t), 10.70 (1H, s), 11.56 (1H, s), 12.63 (1H, br s), 13.25 (1H, brs); IR (solid) 3294, 3271, 3093, 1641, 1586, 1568, 1550, 1513, 1481,1413, 1336, 1158, 999; MS 356.2 (M+H)⁺

Example 95[2-(3-Hydroxymethylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-16):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp >250° C.; ¹H NMR (DMSO) δ2.20 (3H, s), 4.53 (2H,s), 5.22 (1H, br s), 6.31 (1H, br s), 7.24 (1H, d), 7.33-7.53 (4H, m),7.61 (1H, d), 7.86 (1H, t), 8.67 (1H, d), 10.61 (1H, br s), 11.52 (1H,br s), 12.59 (1H, br s), 13.10 (1H, br s); IR (solid) 3401, 3209, 3108,3071, 2975, 2916, 1632, 1609, 1595, 1554, 1485, 1421, 1371, 1348, 1046,1005, 813; MS 347.3 (M+H)⁺

Example 96[2-(3-Hydroxyphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-17):

Prepared in a manner similar to the above described Method A to afford awhite solid, mp >250° C.; ¹H NMR (DMSO) δ2.22 (3H, s), 6.42 (1H, br s),6.72 (1H, d), 6.97 (2H, s), 7.21 (1H, t), 7.47 (1H, t), 7.60 (1H, d),7.85 (1H, t), 8.67 (1H, d), 9.76 (1H, s), 10.53 (1H, s), 11.53 (1H, s),12.58 (1H, br s), 12.99 (1H, br s); IR (solid) 3354, 3027, 2893, 2817,1654, 1588, 1541, 1490, 1436, 1418, 1332, 1154, 1004; MS 333.2 (M+H)⁺

Example 97

(5-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenylamino-quinazolin-4-yl)-amine(IIc-18):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 234° C.; ¹H NMR (DMSO) δ0.74 (2H, s), 0.92 (2H,s), 1.91 (1H, s), 5.83 and 6.54 (1H, 2×br s), 6.94 (1H, t), 7.30 (3H,m), 7.50 (1H, s), 7.65 (1H, s), 7.91 (2H, d), 8.27 (1H, s), 9.13 and9.77 (1H, 2×br s), 10.07 and 10.52 (1H, 2×br s), 12.19 and 12.82 (1H,2×br s); IR (solid) 3443, 1622, 1595, 1577, 1554, 1486, 1449, 1413,1376, 1340, 1235, 1171, 988, 806; MS 343.2 (M+H)⁺

Example 98(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methylphenylamino)-quinazolin-4-yl]-amine(IIc-19):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 117° C.; ¹H NMR (DMSO) δ0.72 (2H, s), 0.92 (2H,s), 1.90 (1H, m), 2.32 (3H, s), 6.20 (1H, br s), 6.80 (1H, d), 7.20 (1H,t), 7.27 (1H, br s), 7.51 (1H, br s), 7.55-7.85 (3H, m), 8.43 (1H, brs), 9.50 (1H, br s), 10.44 (1H, s), 12.55 (1H, br s); IR (solid) 3303,1618, 1581, 1554, 1536, 1495, 1472, 1436, 1413, 1372, 1336, 1240, 990;MS 357.4 (M+H)⁺

Example 99(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(6-methoxypyridin-3-ylamino)-quinazolin-4-yl]-amine(IIc-20):

Prepared in a manner similar to the above described Method A to afford apink solid, mp 120° C.; ¹H NMR (DMSO) δ0.72 (2H, s), 0.91 (2H, s), 1.89(1H, m), 3.85 (3H, s), 6.20 (1H, br s), 6.82 (1H, d), 7.25 (1H, s), 7.48(1H, m), 7.66 (1H, t), 8.13 (1H, br s), 8.42 (1H, br s), 8.61 (1H, brs), 9.50 (1H, br s), 10.48(1H, br s), 12.55 (1H, br s); IR (solid) 3457,3439, 1622, 1604, 1577, 1554, 1481, 1422, 1386, 1363, 1272, 1235, 1035,985, 821; MS 374.2 (M+H)⁺

Example 100(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(indan-5-ylamino)-quinazolin-4-yl]-amine(IIc-21):

Prepared in a manner similar to the above described Method A to afford apale brown solid, mp 199-204° C.; ¹H NMR (DMSO) δ0.69 (2H, br s), 0.91(2H, br s), 1.90 (1H, m), 2.02 (2H, m), 2.68 (1H, m), 2.83 (3H, m), 6.46(1H, br s), 7.18 (1H, d), 7.26 (1H, br s), 7.50 (1H, d), 7.67 (1H, t),7.75 (1H, br s), 8.45 (1H, br s), 9.70 (1H, br s), 10.60 (1H, br s),12.30 and 12.80 (1H, 2×br s); IR (solid) 1621, 1601, 1572, 1552, 1495,1474, 1439, 1425, 1408, 1382, 1363, 1319, 1267; MS 383.3 (M+H)⁺

Example 101(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(1H-indol-6-ylamino)-quinazolin-4-yl]-amine(IIc-22):

Prepared in a manner similar to the above described Method A to afford adark brown solid, mp >300° C.; ¹H NMR (DMSO) δ0.69 (2H, br s), 0.89 (2H,br s), 1.88 (1H, m), 5.77 and 6.74 (1H, 2×br s), 6.35 (1H, s), 7.22 (3H,br s), 7.45 (2H, d), 7.65 (1H, s), 8.35 (2H, br s), 8.86, 9.70 and 10.01(1H, 3×br s), 10.49, 12.12 and 12.84 (1H, 3×br s), 10.94 (s, 1H); IR(solid) 1623, 1603, 1571, 1549, 1495, 1477, 1460, 1419, 1383, 1336,1264, 1250, 1238; MS 382.4 (M+H)⁺

Example 102[2-(4-Acetamido-3-methylphenylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-23):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp >188° C. (dec.); ¹H NMR (DMSO) δ0.72 (2H, br s),0.94 (2H, br s), 1.92 (1H, m), 2.03 (3H, s), 2.19 (3H, s), 5.80 and 6.69(1H, 2×br s), 7.22 (2H, br s), 7.49 (1H, br s), 7.70 (3H, m), 8.35 (1H,br s), 9.01, 9.59 and 10.01 (1H, 3×br s), 9.19 (1H, s), 10.53, 12.16 and12.81 (1H, 3×br s); IR (solid) 1637, 1624, 1578, 1542, 1502, 1474, 1428,1403, 1343, 1320, 1307, 1250; MS 414.4 (M+H)⁺

Example 103[2-(4-Chloro-3-methylphenylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-24):

Prepared in a manner similar to the above described Method A to afford apale brown solid, mp 244-246° C.; ¹H NMR (DMSO) δ0.69 (2H, br s), 0.94(2H, br s), 1.91 (1H, m), 2.32 (3H, s), 5.89 and 6.63 (1H, 2×br s), 7.28(2H, m), 7.49 (1H, m), 7.65 (1H, m), 7.80 (1H, br s), 7.86 (1H, s), 8.40(1H, br s), 9.17, 9.81 and 10.06 (1H, 3×br s), 10.58, 12.19 and 12.78(1H, 3×br s); IR (solid) 1615, 1578, 1549, 1475, 1419, 1397, 1365, 1331,1296, 1261, 1238, 1187, 1139; MS 391.4 (M+H)⁺

Example 104(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-ethylphenylamino)-quinazolin-4-yl]-amine(IIc-25):

Prepared in a manner similar to the above described Method A to afford apale brown solid, mp 250-251° C.; ¹H NMR (DMSO) δ0.72 (2H, br s), 0.91(2H, br s), 1.19 (3H, t), 1.91 (1H, m), 2.58 (2H, q), 5.81 and 6.64 (1H,2×br s), 7.15 (2H, d), 7.22 (1H, s), 7.47 (1H, s), 7.64 (1H, s), 7.78(2H, s), 8.36 (1H, br s), 9.03, 9.66 and 10.05 (1H, 3×br s), 10.49,12.20 and 12.80 (1H, 3×br s); IR (solid) 1603, 1574, 1546, 1509, 1497,1474, 1439, 1417, 1386; MS 371.5 (M+H)⁺

Example 105(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-propylphenylamino)-quinazolin-4-yl]-amine(IIc-26):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 255-256° C.; ¹H NMR (DMSO) δ0.72 (2H, br s), 0.91(5H, t), 1.60 (2H, m), 1.90 (1H, m), 2.58 (2H, q), 5.81 and 6.63 (1H,2×br s), 7.12 (2H, d), 7.21 (1H, s), 7.47 (1H, s), 7.63 (1H, s), 7.77(2H, s), 8.36 (1H, br s), 9.01, 9.70 and 10.11 (1H, 3×br s), 10.51,12.17 and 12.80 (1H, 3×br s); IR (solid) 1595, 1571, 1545, 1499, 1477,1442, 1413, 1388; MS 385.6 (M+H)⁺

Example 106(5-Cyclopropyl-2H-pyrazol-3-yl)-{2-[4-(2-hydroxyethyl)phenylamino]-quinazolin-4-yl}-amine(IIc-27):

Prepared in a manner similar to the above described Method A to afford apale brown solid, mp 255-256° C.; ¹H NMR (DMSO) δ0.73 (2H, br s), 0.91(5H, t), 1.90 (1H, m), 2.69 (2H, t), 3.60 (2H, q), 4.62 (1H, t), 5.81and 6.65 (1H, 2×br s), 7.15 (2H, d), 7.22 (1H, s), 7.46 (1H, s), 7.63(1H, s), 7.77 (2H, s), 8.36 (1H, br s), 9.05, 9.69 and 10.02 (1H, 3×brs), 10.52, 12.17 and 12.79 (1H, 3×br s); IR (solid) 1632, 1569, 1546,1483, 1452, 1434, 1402, 1371, 1267, 1231; MS 387.4 (M+H)⁺

Example 107(5-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenetylamino-quinazolin-4-yl)-amine(IIc-28):

Prepared in a manner similar to the above described Method A to afford awhite solid, mp >250° C.; ¹H NMR (DMSO) δ0.66 (2H, m), 0.84 (2H, m),1.83 (1H, m), 2.90 (2H, t), 3.56 (2H, m), 6.29 (1H, br s), 7.01 (1H, t),7.12-7.38 (6H, m), 7.48 (1H, t), 8.42 (1H, s), 10.91 (1H, br s), 13.11(1H, br s); IR (solid) 2922, 1650, 1627, 1577, 1550, 1500, 1482, 1395,1368, 1004, 832; MS 371.3 (M+H)⁺

Example 108[2-(2-Cyclohexylethylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-29):

Prepared in a manner similar to the above described Method A to afford awhite solid, mp >250° C.; ¹H NMR (DMSO) δ0.70 (2H, s), 0.80-1.00 (4H,m), 1.05-1.30 (4H, m), 1.30-1.50 (3H, m), 1.55-1.80 (5H, m), 1.87 (1H,s), 5.40-6.70 (2H, br s), 7.04 (1H, s), 7.25 (1H, s), 7.49 (1H, s), 8.25(1H, s), 10.06 (1H, br s), 11.93 (1H, br s); IR (solid) 3448, 2920,2852, 1618, 1600, 1568, 1550, 1486, 1418, 1395, 1367, 1258, 1008, 985;MS 377.4 (M+H)⁺

Example 109[2-(4-Carboxymethoxyphenylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-30):

Prepared in a manner similar to the above described Method A to afford ayellow solid, mp >250° C.; ¹H NMR (DMSO) 0.72 (2H, m), 0.91 (2H, m),1.90 (1H, m), 4.62 (2H, s), 6.24 (1H, s), 6.88 (2H, s), 7.21 (1H, m),7.45 (1H, m), 7.62 (1H, m), 7.78 (2H, m), 8.35 (1H, m), 9.31 (1H, s),10.25 (1H, s), 11.70 (1H, br s); IR (solid) 1663, 1595, 1563, 1509,1422, 1331, 1240, 1176, 1053, 999; MS 417.3 (M+H)⁺

Example 110[2-(4-Cyanomethylphenylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-31):

Prepared in a manner similar to the above described Method A to afford awhite solid, mp 222° C.; ¹H NMR (DMSO) δ0.74 (2H, m), 0.93 (2H, m), 1.92(1H, m), 3.97 (2H, s), 5.82 and 6.65 (1H, 2×br s), 7.29 (3H, m), 7.50(1H, m), 7.66 (1H, m), 7.92 (2H, m), 8.39 (1H, m), 9.21 and 9.85 (1H,2×br s), 9.90 and 10.56 (1H, 2×s), 12.19 and 12.80 (1H, 2×br s); IR(solid) 1641, 1622, 1595, 1581, 1554, 1513, 1486, 1463, 1408, 1372, 985,821; MS 382.3 (M+H)⁺

Example 111[2-(Benzothiazol-6-ylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-32):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 255-256° C.; ¹H NMR (DMSO) δ0.73 (2H, m), 0.92(2H, m), 1.92 (1H, m), 5.83 and 6.63 (1H, 2×br s), 7.27 (1H, br s), 7.59(1H, br s), 7.68 (1H, br s), 7.79 (1H, br s), 7.98 (1H, br s), 8.41 (1H,br s), 8.97 (1H, br s), 9.19 (1H, s), 9.58 and 10.10 (1H, 2×br s),10.57, 12.21 and 12.85 (1H, 3×br s); IR (solid) 1624, 1592, 1575, 1512,1472, 1411, 1377, 1333, 1244; MS 400.3 (M+H)⁺

Example 112(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dimethylphenylamino)-quinazolin-4-yl]-amine(IIc-33):

Prepared in a manner similar to the above described Method A to afford awhite solid, mp 245-246° C.; ¹H NMR (DMSO) δ0.72 (2H, br s), 0.90 (2H,br s), 1.90 (1H, m), 2.18 (3H, s), 2.23 (3H, s), 5.77 and 6.63 (1H, 2×brs), 7.09 (1H, d), 7.23 (1H, br s), 7.47 (1H, br s), 7.59 (1H, br s),7.64 (1H, br s), 8.36 (1H, br s), 9.02, 9.55 and 10.07 (1H, 3×br s),10.49, 12.31 and 12.80 (1H, 3×br s); IR (solid) 1620, 1600, 1574, 1552,1497, 1474, 1436, 1416, 1385, 1262; MS 371.5 (M+H)⁺

Example 113(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2-phenoxyethylamino)-quinazolin-4-yl]-amine(IIc-34):

Prepared in a manner similar to the above described Method A to afford awhite solid, mp 203° C.; ¹H NMR (DMSO) δ0.70 (2H, m), 0.88 (2H, m), 1.87(1H, m), 3.73 (2H, d), 4.16 (2H, s), 5.75 and 6.70 (1H, 2×br s), 6.93(1H, t), 6.90-7.20 (3H, m), 7.20-7.45 (3H, m), 7.55 (1H, s), 7.76 (1H,br s), 8.32 (1H, s), 9.95 and 10.35 (1H, 2×s), 12.13 and 12.75 (1H, 2×brs); IR (solid) 3434, 1622, 1600, 1572, 1554, 1499, 1476, 1422, 1399,1385, 1303, 1267, 1226, 1212, 1052, 829; MS 387.4 (M+H)⁺

Example 114(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(thiophen-2-methylamino)-quinazolin-4-yl]-amine(IIc-35):

Prepared in a manner similar to the above described Method A to afford awhite solid, mp 212° C.; ¹H NMR (DMSO) δ0.67 (2H, m), 0.90 (2H, m), 1.86(1H, m), 4.74 (2H, d), 5.76 and 6.66 (1H, 2×br s), 6.95 (1H, s),6.90-7.20 (2H, m), 7.20-8.45 (5H, m), 9.94 and 10.40 (1H, 2×s), 12.13and 12.71 (1H, 2×br s); IR (solid) 3444, 2948, 2847, 1622, 1600, 1559,1500, 1481, 1418, 1390, 1358, 1336, 1313, 1263, 1217, 1185, 1149, 990,821; MS 363.4 (M+H)⁺

Example 115[2-(4-Carboxymethylphenylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-36):

Prepared in a manner similar to the above described Method A to afford abrown solid, mp >210° C. (dec.); ¹H NMR (DMSO) δ0.64 (2H, br s), 0.92(2H, m), 1.92 (1H, m), 3.50 (2H, s), 5.76 and 6.54 (1H, 2×s), 7.19 (1H,s), 7.24 (1H, m), 7.49 (1H, d), 7.64 (1H, t), 7.84 (2H, d), 8.37 (1H,m), 10.27 and 12.25 (1H, 2×br s); IR (solid) 1648, 1591, 1555; 1512,1489, 1428, 1411, 1374; MS 401.4 (M+H)⁺

Example 116(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(1H-indazol-5-ylamino)-quinazolin-4-yl]-amine(IIc-37):

Prepared in a manner similar to the above described Method A to afford apurple solid, mp 268-271° C.; ¹H NMR (DMSO) δ0.69 (2H, br s), 0.90 (2H,m), 1.88 (1H. m), 5.86 and 6.58 (1H, 2×s), 7.22 (1H, s), 7.61 (1H, s),7.71 (2H, m), 8.01 (1H, s), 8.37 (2H, s), 8.58, 9.05 and 9.58 (1H, 3×brs), 10.01, 10.68 and 12.38 (1H, 3×br s), 12.90 (1H, s); IR (solid) 1626,1605, 1576, 1546, 1512, 1495, 1476, 1447, 1431, 1416, 1393, 1261, 1224;MS 383.3 (M+H)⁺

Example 117(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(pyridin-3-ylmethylamino)-quinazolin-4-yl]-amine(IIc-38):

Prepared in a manner similar to the above described Method A to afford ayellow solid, mp 193° C.; ¹H NMR (DMSO) δ0.69 (2H, m), 0.89 (2H, m),1.86 (1H, m), 4.60 (2H, s), 5.76, 6.22 and 6.66 (1H, 3×br s), 7.10 (1H,s), 7.33 (2H, s), 7.54 (1H, s), 7.78 (1H, s), 8.31 (1H, s), 8.44 (1H,s), 8.61 (1H, s), 10.00 and 10.32 (1H, 2×s), 12.15 and 12.63 (1H, 2×brs); IR (solid) 2927, 2850, 1623, 1600, 1577, 1536, 1477, 1418, 1332,1254, 814; MS 358.3 (M+H)⁺

Example 118(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxycarbonylphenylamino)-quinazolin-4-yl]-amine(IIc-39):

Prepared in a manner similar to the above described Method A to afford awhite solid, mp 228-231° C.; ¹H NMR (DMSO) δ0.73 (2H, br s), 0.91 (2H,m), 1.92 (1H, m), 3.88 (3H, s), 5.99 and 6.79 (1H, 2×s), 7.27 (1H, s),7.46 (3H, m), 7.68 (1H, s), 8.36 (1H, d), 8.48 (2H, s), 9.36, 9.84 and10.00 (1H, 3×br S), 10.63, 12.17 and 12.79 (1H, 3×br s); IR (solid)1716, 1615, 1591, 1579, 1557, 1473, 1432, 1416, 1379, 1334, 1298, 1276,1226, 1191, 1142, 1110, 1020, 985; MS 401.3 (M+H)⁺

Example 119[2-(3-Carboxyphenylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-40):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 298-302° C.; ¹H NMR (DMSO) δ0.73 (2H, br s), 0.91(2H, m), 1.90 (1H, m), 7.26 (1H, s), 7.35 (1H, t), 7.50 (2H, d), 7.66(1H, t), 8.31 (2H, m), 8.41 (1H, d); IR (solid) 1661, 1597, 1578, 1558,1517, 1486, 1424, 1385; MS 387.3 (M+H)⁺

Example 120(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-ethylphenylamino)-guinazolin-4-yl]-amine(IIc-41):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 186-188° C.; ¹H NMR (DMSO) δ0.73 (2H, br s), 0.91(2H, br s), 1.22 (3H, t), 1.90 (1H, m), 2.62 (2H, d), 5.81 and 6.70 (1H,2×br S), 6.78 (1H,d), 7.20 (2H, s), 7.48 (1H, s), 7.65 (1H, s), 7.69(1H, s), 7.81 (1H, s), 8.38 (1H, br s), 9.03, 9.74 and 10.03 (1H, 3×brs), 10.55, 12.16 and 12.82 (1H, 3×br s); IR (solid) 1614, 1580, 1549,1534, 1493, 1471, 1433, 1409, 1374, 1340, 1240, 1182, 1165, 1138; MS371.3 (M+H)⁺

Example 121(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,3-dimethylphenylamino)-quinazolin-4-yl]-amine(IIc-42):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 241-242° C.; ¹H NMR (DMSO) δ0.58 (2H, br s), 0.86(2H, d), 1.77 (1H, br s), 2.11 (3H, br s), 2.28 (3H, s), 5.77 and 6.14(1H, 2×br s,), 7.01 (1H, s), 7.11 (1H, t), 7.22 (1H, br s), 7.29 (1H,d), 7.56 (1H, s), 8.36 (1H, br s), 8.49, 8.98 and 9.98 (1H, 3×br s),10.48, 12.04 and 12.68 (1H, 3×br s); IR (solid) 1622, 1603, 1573, 1552,1495, 1471, 1440, 1428, 1412, 1384, 1268; MS 371.4 (M+H)⁺

Example 122(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dimethoxyphenylamino)-quinazolin-4-yl]-amine(IIc-43):

Prepared in a manner similar to the above described Method A to afford agrey solid, mp 144° C.; ¹H NMR (DMSO) δ0.69 (2H, s), 0.86 (2H, d), 1.89(1H, m), 3.61 (3H, s), 3.67 (3H, s), 5.76 (1H, br s), 6.12 (1H, d), 6.31(1H, s), 6.66 (1H, d), 6.94 (1H, d), 7.27 (1H, t), 7.50 (1H, d), 7.68(1H, t), 8.45 and 9.36 (1H, br s, rotamers), 9.42 and 10.54 (1H, s,rotamers), 12.29 and 12.82 (1H, br s, rotamers); IR (solid) 3331, 3000,2959, 2931, 2836, 1627, 1604, 1577, 1536, 1509, 1463, 1441, 1418, 1336,1259, 1232, 1200, 1027; MS 403.8 (M+H)⁺

Example 123(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxyphenylamino)-quinazolin-4-yl]-amine(IIc-44):

Prepared in a manner similar to the above described Method A to afford agrey solid, mp 207-211° C.; ¹H NMR (DMSO) δ0.73 (2H, br s), 0.91 (2H, brs), 1.91 (1H, m), 3.77 (3H, s), 5.81 and 6.71 (1H, 2×br s), 6.53 (1H,d), 7.19-7.85 (7H, m), 8.34 (1H, s), 9.08, 9.79 and 10.06 (1H, 3×br s),10.56, 12.16 and 12.82 (1H, 3×br s); IR (solid) 1611, 1580, 1549, 1533,1498, 1477, 1430, 1409, 1374, 1337, 1253, 1204, 1180, 1157, 1141, 1041,1030, 992; MS 373.7 (M+H)⁺

Example 124(5-Methyl-2H-pyrazol-3-yl)-(2-phenylamino-5,6,7,8-tetrahydroquinazolinin-4-yl)-amine(IIc-45):

Prepared in a manner similar to the above described Method C.

Example 125[2-(Biphenyl-3-ylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-46):

Prepared in a manner similar to the above described Method A to afford apale brown solid, mp 153° C.; ¹H NMR (DMSO) δ0.73 (2H, s), 0.90 (2H, d),1.89 (1H, m), 5.83 and 6.70 (1H, br s, rotamers), 7.25 (2H, d), 7.32(2H, m), 7.50 (3H, t), 7.68 (3H, m), 8.00 (1H, d), 8.22 (1H, br s), 8.40(1H, br s), 9.20 and 9.89 (1H, br s, rotamers), 10.06 and 10.46 (1H, s,rotamers), 12.17 and 12.84 (1H, br s, rotamers); IR (solid) 3333, 1627,1609, 1581, 1540, 1504, 1472, 1449, 1426, 1335, 1248, 1216, 1102, 988,819; MS 419.3 (M+H)⁺

Example 126(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-phenylprop-1-ylamino)-quinazolin-4-yl]-amine(IIc-47):

Prepared in a manner similar to the above described Method A to afford awhite solid, mp 189° C.; ¹H NMR (DMSO) δ0.71 (2H, s), 0.91 (2H, s), 1.89(3H, s), 2.69 (2H, s), 3.37 (2H, s), 5.76 and 6.66 (1H, br s, rotamers),6.95-7.60 (8H, m), 8.10-8.40 (1H, m), 9.89 and 10.30 (1H, br s,rotamers), 12.10 and 12.75 (1H, br s, rotamers); IR (solid) 1622, 1595,1572, 1545, 1499, 1481, 1417, 1390, 1367, 1048, 997, 829; MS 385.4(M+H)⁺

Example 127[2-(4-acetamido-3-methylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-48):

Prepared in a manner similar to the above described Method-A to afford apale brown solid, mp 251° C.; ¹H NMR (DMSO) δ2.04 (3H, s), 2.19 (3H, s),2.56 (3H, s), 5.92 and 6.80 (1H, br s, rotamers), 7.22 (2H, s), 7.48(1H, s), 7.64 (1H, s), 7.73 (2H, s), 8.40 (1H, s), 9.05 and 9.74 (1H, brs, rotamers), 9.20 (1H, s), 10.05 and 10.54 (1H, br s, rotamers), 12.15and 12.82 (1H, br s, rotamers); IR (solid) 3309, 2972, 2936, 1641, 1604,1577, 1536, 1504, 1468, 1423, 1409, 1377, 1341, 1304, 1259, 1223, 1100,1009, 864; MS 388.2 (M+H)⁺

Example 128(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(indan-2-ylamino)-quinazolin-4-yl]-amine(IIc-49):

Prepared in a manner similar to the above described Method A to afford abrown solid, mp 233-234° C.; ¹H NMR (DMSO) δ0.65 (2H, s), 0.84 (2H, s),1.83 (1H, s), 2.91 (2H, m), 3.33 (2H, s), 4.72 (1H, s), 6.07 (1H, br s),7.00-7.60 (8H, m), 8.29 (1H, s), 10.30 (1H, br s), 12.24 (1H, br s); IR(solid) 3425, 2941, 2836, 1622, 1595, 1572, 1540, 1495, 1476, 1426,1394, 1248, 1025, 1007, 870, 833; MS 383.3 (M+H)⁺

Example 129[2-(3-Methylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-50):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 240-242° C.; ¹H NMR (DMSO) δ2.25 (3H, s), 2.30(3H, s), 5.95 (1H, br s), 6.76 (1H, d), 7.10-7.35 (2H, m), 7.48 (1H, s),7.55-7.85 (3H, m), 8.40 (1H, s), 9.05 and 9.74 (1H, br s, rotamers),10.07 and 10.55 (1H, br s, rotamers), 12.14 and 12.81 (1H, br s,rotamers); IR (solid) 3443, 2914, 2859, 1622, 1586, 1549, 1536, 1481,1445, 1408, 1372, 1330, 1267, 1239, 1184, 1166, 1139, 993, 838, 806; MS331.3 (M+H)⁺

Example 130[2-(2-Chloro-5-methylphenylamino)-guinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-51):

Prepared in a manner similar to the above described Method A to afford agrey solid, mp 246-247° C.; ¹H NMR (DMSO) δ2.19 (3H, s), 2.31 (3H, s),6.37 (1H, br s), 6.94 (1H, d), 7.23 (1H, s), 7.37 (1H, d), 7.43 (1H, d),7.64 (1H, t), 7.97 (1H, s), 8.19 (1H, s), 8.42 (1H, br s), 10.17 (1H, brs), 12.19 (1H, br s); IR (solid) 3409, 2918, 2850, 1627, 1591, 1573,1545, 1513, 1486, 1463, 1418, 1386, 1332, 1291, 1259, 1182, 1000, 827;MS 365.2 (M+H)⁺

Example 131(5-Cyclopropyl-2H-pyrazol-3-yl)-{2-[4-(morpholin-1-yl)phenylamino]-quinazolin-4-yl}-amine(IIc-52):

Prepared in a manner similar to the above described Method A to afford agrey solid, mp 275-276° C.; ¹H NMR (DMSO) δ0.71, (2H, s), 0.90 (2H, s),1.89 (1H, s), 3.05 (4H, s), 3.75 (4H, s), 5.78 and 6.61 (1H, br s,rotamers), 6.93 (2H, s), 7.20 (1H, s), 7.43 (1H, s), 7.50-7.90 (3H, m),8.39 (1H, s), 8.95 and 9.58 (1H, br s, rotamers), 10.07 and 10.47 (1H,br s, rotamers), 12.16 and 12.81 (1H, br s, rotamers); IR (solid) 3245,2990, 2972, 2959, 2936, 2918, 1618, 1577, 1559, 1509, 1477, 1445, 1413,1382, 1264, 1223, 1150, 1109, 1050, 923, 882, 823; MS 428.3 (M+H)⁺

Example 132[2-(Benzothiazol-6-ylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-53):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 236-239° C.; ¹H NMR (DMSO) δ2.25 (3H, s), 6.35(1H, br s), 7.22 (1H, t), 7.53 (1H, d), 7.62 (1H, t), 7.76 (1H, d), 7.98(1H, d), 8.39 (1H, d), 9.05 (1H, s), 9.17 (1H, s), 9.59 (1H, br s),10.30 (1H, br s), 12.35 (1H, br s); IR (solid) 1622, 1605, 1567, 1546,1505, 1473, 1441, 1417, 1385, 1341, 1297, 1273, 1253, 1192, 1130; MS374.1 (M+H)⁺

Example 133[2-(3,4-Dimethylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-54):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 249-251° C.; ¹H NMR (DMSO) δ2.18 (3H, br s), 2.21(3H, br s), 2.24 (3H, br s), 5.92 and 6.80 (1H, 2×br s), 7.05 (1H, brs), 7.21 (1H, br s), 7.46 (1H, br s), 7.64 (3H, br s), 8.37 (1H, br s),9.00, 9.51 and 9.73 (1H, 3×br s), 10.12, 10.54 and 12.17 (1H, 3×br s);IR (solid) 1616, 1582, 1547, 1505, 1473, 1452, 1413, 1368, 1334, 1294,1246, 1210, 1188, 1170, 1139; MS 345.3 (M+H)⁺

Example 134[2-(3-Ethylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-55):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 238-239° C.; ¹H NMR (DMSO) δ1.21 (3H, t), 2.25(3H, br s), 2.61 (2H, q), 5.92 and 6.80 (1H, 2×br s), 6.78 (1H, d), 7.21(2H, br s), 7.48 (1H, br s), 7.65 (1H, s), 7.72 (1H, s), 7.80 (1H, s),8.40 (1H, br s), 9.09, 9.58 and 10.10 (1H, 3×br s), 10.54, 12.26 and12.81 (1H, 3×br s); IR (solid) 1619, 1556, 1535, 1471, 1441, 1407, 1377,1341, 1274, 1246, 1185, 1167, 1139, 995; MS 345.5 (M+H)⁺

Example 135[2-(3-Methoxyphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-56):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 212-215° C.; ¹H NMR (DMSO) δ2.25 (3H, br s), 3.77(3H, s), 5.92 and 6.84 (1H, 2×br s), 6.55 (1H, d), 7.13 (2H, m),7.41-7.50 (2H, m), 7.65 (1H, s), 7.77 (1H, s), 8.41 (1H, br s), 9.10,9.79 and 10.10 (1H, 3×br s), 10.55, 12.13 and 12.82 (1H, 3×br s); IR(solid) 1610, 1576, 1532, 1494, 1468, 1425, 1337, 1277, 1256, 1201,1159; MS 347.4 (M+H)⁺

Example 136[2-(4-Acetamido-3-cyanophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-57):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 294-296° C.; ¹H NMR (DMSO) δ2.08 (3H, s), 2.28(3H, s), 6.67 (1H, br s), 7.27 (1H, s), 7.43 (1H, d), 7.53 (1H, s), 7.68(1H, s), 8.04 (1H, d), 8.45 (2H, s), 9.41, 10.35 and 12.18 (2H, 3×br s),10.00 (1H, s); IR (solid) 1620, 1583, 1558, 1237, 1508, 1477, 1446,1413, 1373, 1341, 1292, 1259, 1241, 1180, 1162, 1142, 1105, 1030, 1000;MS 399.2 (M+H)⁺

Example 137[2-(2-Methoxybiphenyl-5-ylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-58):

Prepared in a manner similar to the above described Method A to afford awhite solid, 222-223° C.; ¹H NMR (DMSO) δ2.22 (3H, s), 3.75 (3H, s),6.82 (1H, br s), 7.05-7.11 (1H, m), 7.15-7.25 (1H, m), 7.30-7.36 (1H,m), 7.40-7.50 (3H, m), 7.49-7.55 (2H, m), 7.55-7.70 (1H, m), 7.70-7.82(1H, m), 7.90-8.02 (1H, m), 8.30-8.50 (1H, m); IR (solid) 1625, 1604,1574, 1556, 1496, 1473, 1444, 1403, 1384, 1258, 1234, 1182, 1018, 824,806, 755, 698; MS 423.4 (M+H)⁺

Example 138[2-(4-Acetamidophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-59):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 253-256° C.; ¹H NMR (DMSO) δ2.02 (3H, s), 2.25(3H, br s), 5.92 and 6.77 (1H, 2×br s), 7.21 (1H, s), 7.49 (3H, s), 7.63(1H, s), 7.83 (2H, d), 8.38 (1H, br s), 9.03 and 10.05 (1H, 2×br s),9.81 (1H, s), 12.13 and 12.80 (1H, 2×br s); IR (solid) 1669, 1635, 1617,1574, 1535, 1512, 1486, 1422, 1394, 1366, 1316, 1268, 1231, 1184, 1119,1101; MS 374.1 (M+H)⁺

Example 139[2-(4-tert-Butoxycarbonylamino-phenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-60):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 238-242° C.; 1H NMR (DMSO) δ1.48 (9H, s), 2.24(3H, s), 6.23 (1H, br s), 7.12 (1H, s), 7.36 (3H, s), 7.54 (1H, s), 7.67(2H, d), 8.30 (1H, d), 9.14 (2H, br s), 10.24 and 12.19 (1H, 2×br s); IR(solid) 1698, 1620, 1555, 1520, 1475, 1443, 1405, 1371, 1310, 1241,1167, 1055, 996; MS 432.1 (M+H)⁺

Example 140[2-(4-Cyanophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-61):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 293-298° C.; ¹H NMR (DMSO) δ2.25 (3H, s), 6.50(1H, br s), 7.27 (1H, s), 7.51 (1H, s), 7.64 (1H, s), 7.71 (2H, d), 8.40(1H, s), 9.76 (1H, br s), 10.34 (1H, br s), 12.33 (1H, br s); IR (solid)1633, 1605, 1571, 1517, 1505, 1469, 1418, 1337, 1255, 1174, 1000; MS342.1 (M+H)⁺

Example 141(5-Methyl-2H-pyrazol-3-yl)-[2-(6-oxo-6,10b-dihydro-4aH-benzo[c]chromen-2-ylamino)-quinazolin-4-yl]-amine(IIc-62):

Prepared in a manner similar to the above described Method A to afford apale yellow solid, mp 293-298° C.; ¹H NMR (DMSO) δ1.72 (3H, br s), 6.23(1H, br s), 7.50 (1H, t), 7.66 (2H, t), 7.75 (1H, t), 7.87 (1H, t), 7.77(1H, t), 8.26 (1H, d), 8.33 (1H, d), 8.58-8.72 (2H, m), 10.55 (1H, s),11.55 (1H, s), 12.40 (1H, s); IR (solid) 1707, 1629, 1607, 1579, 1540,1497, 1488, 1471, 1446, 1428, 1417, 1346, 1332, 1298, 1270, 1255, 1207,1114, 998, 816, 793, 766, 758, 710, 685; MS 435.4 (M+H)⁺

Example 142[2-(Biphenyl-3-ylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-63):

Prepared in a manner similar to the above described Method A to afford apale brown solid, mp 206-207° C.; ¹H NMR (DMSO) δ2.20 (3H,s), 6.80 (1H,br s), 7.24-7.27 (2H, m), 7.36-7.40 (2H, m), 7.48-7.52 (3H, m),7.67-7.69 (3H, m), 7.94 (1H, m), 8.26 (1H, m), 8.42 (1H, m), 9.30 (1H,br s), 10.16 (1H, br s), 12.13 (1H, br s); IR (solid) 1593, 1578, 1544,1498, 1479, 1414, 1384, 1251, 1209, 1003; MS 393.2 (M+H)⁺

Example 143[2-(4-Methoxycarbonylmethyl-3-methylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-64):

Prepared in a manner similar to the above described Method A to afford awhite solid, mp 245-246° C.; ¹H NMR (DMSO) δ2.23 (3H, s), 2.26 (3H, s),3.63 (3H, s), 3.64 (2H, s), 5.99 (0.5H, br s), 6.80 (0.5 H, br s), 7.10(1H, m), 7.25 (1H, m), 7.50 (1H, m), 7.61-7.80 (3H, m), 8.44 (1H, m),9.10 (0.5H, br s), 9.78 (0.5H, br s), 10.11 (0.5H, br s), 10.56 (0.5H,br s), 12.18 (0.5H, br s), 12.90 (0.5H, br s); IR (solid) 1732, 1710,1622, 1581, 1554, 1538, 1508, 1490, 1446, 1411, 1371, 1336, 1306, 1257,1244, 1204, 1146, 1016, 998, 797, 754, 692; MS 403.4 (M+H)⁺

Example 144[2-(4-Carboxymethyl-3-methylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-65):

A solution of[2-(4-methoxycarbonylmethyl-3-methylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-64, 200 mg, 0.5 mmol) in a mixture of methanol/water (3/1, 8 mL)was treated with 1M NaOH (2 mL, 2 mmol). The mixture was heated at 70°C. for 2 hours and then neutralised with 1M HCl (2 mL, 2 mmol). Thesolid that formed was collected by filtration to afford the titlecompound (185 mg, 95%) as a pale yellow solid, mp 245° C. (dec.); ¹H NMR(DMSO) δ2.27 (6H, 2×s), 3.55 (2H, s), 6.49 (1H, s), 7.13 (1H, d), 7.26(1H, t), 7.50 (1H, d), 7.62-7.78 (3H, m), 8.42 (1H, d), 9.34 (1H,d),10.26 (1H, s), 12.36 (1H, s); IR (solid) 1660, 1590, 1562, 1504, 1427,1385, 810, 776, 751, 693; MS 389.4 (M+H)⁺

Example 145[2-(4-Aminophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-66):

A solution of[2-(4-tert-Butoxycarbonylamino-phenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl(IIc-60, 100 mg, 0.232 mmol) in a mixture of DCM/TFA (5/1, 12 mL) wasstirred for 2 hours at room temperature. The solvents were removed invacuo and the residue triturated in aqueous K₂CO₃. The resulting solidwas collected by filtration and washed with diethyl ether to affordIIc-66 (69 mg, 90%) as an off-white solid, mp 164-167° C.; ¹H NMR (DMSO)δ2.24 (3H, s), 6.33 (1H, br s), 7.12 (2H, d), 7.48 (3H, m), 7.58 (1H,d), 7.86 (1H, t), 8.64 (1H, d), 10.86 (1H, br s), 11.46 (1H, s); IR(solid) 1681, 1512, 1496, 1433, 1415, 1187, 1129; MS 332.4 (M+H)⁺

Example 146[2-(4-Bromophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-67):

Prepared in a manner similar to the above described Method A to affordan off-white solid, mp 290-293° C.; ¹H NMR (DMSO) δ2.27 (3H, s), 6.71(1H, br s), 7.22 (1H, m), 7.46-7.50 (3H, m), 7.66 (1H, m), 7.92-7.94(2H, m), 8.38 (1H, m), 9.28, 10.11 and 12.13 (3H, 3×br s); IR (solid)1619, 1572, 1548, 1486, 1436, 1409, 1372, 1238, 1186, 1136, 1071, 997;MS 395.1/397.1 (M+H)⁺

Example 147[2-(4-Isobutyrylamino-phenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-68):

Prepared in a manner similar to the above described Method A to afford ayellow solid, mp 176-179° C.; ¹H NMR (DMSO) δ1.11 (6H, d), 2.15 (3H, s),2.62 (1H, m), 6.25 (1H, br s), 7.41 (1H, d), 7.46 (1H, t), 7.63 (1H, d),7.71 (2H, d), 7.84 (1H, t), 8.64 (1H, d), 10.00 (1H, s), 10.34 (1H, brs), 11.47 (1H, br s), 12.47 (1H, br s); IR (solid) 1676, 1653, 1585,1561, 1512, 1423, 1407, 1312, 1199, 1177, 1128; MS 402.3 (M+H)⁺

Example 148(5-Ethyl-2H-pyrazol-3-yl)-[2-(5-ethyl-2H-pyrazol-3-ylamino)-quinazolin-4-yl]-amine(IIc-69):

To a solution of 2,4-dichloroquinazoline (0.5 g, 2.51 mmol) and3-amino-5-ethylpyrazole (558 mg, 5.02 mmol) in ethanol (10 mL) was addedtriethylamine (0.35 mL, 2.51 mmol) and the resulting mixture was stirredfor 3 hours at room temperature. The resulting pale yellow precipitatewas collected by filtration, washed with cold ethanol and dried undervacuum to afford IIc-69 (306 mg, 35%) as an off-white solid, mp 248-252°C.; ¹H NMR (DMSO) δ1.30 (m, 6H), 2.72 (m, 4H), 6.12 (br.s, 1H), 6.54 and6.90 (br. s, 1H), 7.58 (t, 1H), 7.74 (d, 1H), 7.90 (t, 1H), 8.78 (d,1H); IR (solid) 1639, 1602, 1591, 1555, 1418; MS 349.2 (M+H)⁺

Example 149 (1H-Indazol-3-yl)-(2-phenylamino-quinazolin-4-yl)-amine(IIc-70):

Prepared in a manner similar to the above described Method A to afford awhite solid; ¹H NMR (DMSO) δ6.90 (m, 3H), 7.11 (t, 1H), 7.19 (m, 2H),7.44 (t, 1H), 7.57 (m, 1H), 7.62 (d, 1H), 7.67 (d, 2H), 7.71 (d, 1H),7.93 (t, 1H), 8.59 (d, 1H), 11.55 (br. s, 1H), 13.15 (s, 1H); MS 353.2(M+H)⁺

Example 150(1H-Indazol-3-yl)-[2-(3-trifluoromethylphenylamino)-quinazolin-4-yl]-amine(IIc-71):

Prepared in a manner similar to the above described Method A to afford apale yellow solid. ¹H NMR (DMSO) δ7.00 (t, 1H), 7.02 (d, 1H), 7.22 (d,1H), 7.37 (td, 1H), 7.56 (m, 3H), 7.61 (d, 1H), 7.66 (d, 2H), 7.92 (t,1H), 8.60 (d, 1H), 10.61 (br. s, 1H), 11.42 (br. s, 1H), 13.12 (s, 1H);MS 421.2 (M+H)⁺

Example 151(1H-Indazol-3-yl)-[2-(4-trifluoromethylphenylamino)-quinazolin-4-yl]-amine(IIc-72):

Prepared in a manner similar to the above described Method A to afford apale yellow solid. ¹H NMR (DMSO) δ7.08 (t, 1H), 7.16 (d, 2H), 7.44 (m,3H), 7.58 (t, 1H), 7.6 (t, 2H), 7.69 (d, 1H), 7.95 (t, 1H), 8.62 (d,1H), 10.82 (br. s, 1H), 11.50 (br. s, 1H), 12.20 (s, 1H); MS 421.2(M+H)⁺

Example 152[2-(Adamantan-2-ylamino)-quinazolin-4-yl]-(1H-indazol-3-yl)-amine(IIc-73):

Prepared in a manner similar to the above described Method A to afford awhite solid. ¹H NMR (DMSO) δ0.83 (br. s, 1H), 0.85 (br. s, 1H), 1.44 (m,4H), 1.55 (m, 3H), 1.63 (s, 2H), 1.73 (s, 1H), 1.82 (s, 1H), 1.84 (s,1H), 3.56 (m, 1H), 7.10 (t, 1H), 7.41 (t, 1H), 7.51 (t, 1H), 7.54 (d,1H), 7.57 (d, 1H), 7.69 (d, 1H), 7.90 (t, 1H), 8.45 (d, 1H), 8.58 (d,1H), 11.60 (s, 1H), 13.10 (s, 1H); MS 411.3 (M+H)⁺

Example 153(1H-Indazol-3-yl)-(2-methyl-phenyl-amino-quinazolin-4-yl)-amine(IIc-74):

Prepared in a manner similar to the above described Method A to afford awhite solid; ¹H NMR (DMSO) δ3.27 (s, 1H), 6.88 (t, 1H), 6.93 (t, 2H),7.04 (t, 1H), 7.14 (d, 2H), 7.22 (t, 1H), 7.36 (m, 2H), 7.48 (d, 1H),7.54 (d, 1H), 7.62 (t, 1H), 8.37 (d, 1H), 10.11 (s, 1H), 12.71 (s, 1H);MS 367.2 (M+H)⁺

Example 154[2-(2-Chloro-phenyl)-amino-quinazolin-4-yl]-(1H-indazol-3-yl)-amine(IIc-75):

Prepared in a manner similar to the above described Method A to afford awhite solid. ¹H NMR (DMSO) δ6.81 (t, 1H), 6.87 (td, 1H), 7.07 (t, 1H),7.34 (dd, 1H), 7.35 (t, 1H), 7.40 (t, 1H), 7.53 (d, 1H), 7.56 (d, 1H),7.63 (d, 2H), 7.72 (t, 1H), 8.07 (d, 1H), 8.46 (d, 1H), 10.37 (s, 1H),12.89 (s, 1H); MS 387.1 (M+H)⁺

Example 155(1H-Indazol-3-yl)-[2-(2-trifluoromethylphenylamino)-quinazolin-4-yl]-amine(IIc-76):

Prepared in a manner similar to the above described Method A to afford awhite solid; ¹H NMR (DMSO) δ7.01 (t, 1H), 7.20 (m, 1H), 7.32 (m, 1H),7.36 (t, 1H), 7.43 (d, 1H), 7.49 (d, 1H), 7.55 (d, 1H), 7.61 (t, 1H),7.64 (d, 1H), 7.69 (d, 1H), 7.95 (t, 2H), 8.62 (d, 1H), 10.15 (m, 1H),11.62 (s, 1H), 13.03 (s, 1H); MS 421.2 (M+H)⁺

Example 156[2-(4-Cyanomethylphenylamino)-quinazolin-4-yl]-(1H-indazol-3-yl)-amine(IIc-77):

Prepared in a manner similar to the above described Method A to afford awhite solid; ¹H NMR (DMSO) δ13.16 (s, 1H), 11.49 (br. s, 1H), 10.38 (br.s, 1H), 8.58 (d, 1H), 7.92 (t, 1H), 7.67 (t, 2H), 7.61 (d, 1H), 7.56 (m,1H), 7.44 (t, 1H), 7.22 (m, 2H), 7.08 (t, 1H), 6.86 (m, 2H), 3.87 (s,2H); MS 392.2 (M+H)⁺

Example 157[2-(4-Chlorophenylamino)-5,6,7,8-tetrahydroquinazolinin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-78):

Prepared in a manner similar to the above described Method C; MS 355.5(M+H)⁺

Example 158(5-Methyl-2H-pyrazol-3-yl)-(2-phenylamino-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl)-amine(IIc-79):

Prepared in a manner similar to the above described Method C; MS 335.3(M+H)⁺

Example 159[2-(Benzimidazol-2-ylamino)-7-benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-80):

Prepared in a manner similar to the above described Method C; MS 452.0(M+H)⁺

Example 160(7-Benzyl-2-phenylamino-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-81):

Prepared in a manner similar to the above described Method C; MS 412.1(M+H)⁺

Example 161[6-Benzyl-2-(4-chlorophenylamino)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-82):

Prepared in a manner similar to the above described Method C; MS 446.3(M+H)⁺

Example 162[2-(Benzimidazol-2-ylamino)-6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-83):

Prepared in a manner similar to the above described Method C; MS 452.2(M+H)⁺

Example 163(6-Benzyl-2-phenylamino-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-84):

Prepared in a manner similar to the above described Method C; MS 411.9(M+H)⁺

Example 164(5-Methyl-2H-pyrazol-3-yl)-(2-phenylamino-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-amine(IIc-85):

Prepared in a manner similar to the above described Method C; MS 322.3(M+H)⁺

Example 165[2-(4-Cyanomethylphenylamino)-quinazolin-4-yl]-(1H-pyrazolo[3,4-b]pyridin-3-yl)-amine(IIc-86):

Prepared in a manner similar to the above described Method A to affordan off-white solid; ¹H NMR (DMSO) δ13.65 (s, 1H), 12.82 (br. s, 1H),11.69 (br. s, 1H), 8.55 (dd, 2H), 8.12 (d, 1H), 7.88 (m, 1H), 7.66 (m,1H), 7.50 (m, 1H), 7.30 (m, 2H), 7.09 (m, 1H), 6.94 (m, 2H), 3.89 (s,2H); MS 393.1 (M+H)⁺.

Example 166[2-(4-Cyanobenzylamino)-quinazolin-4-yl]-(1H-pyrazolo[3,4-b]pyridin-3-yl)-amine(IIc-87):

Prepared in a manner similar to the above described Method A to affordan off-white solid; ¹H NMR (DMSO) δ13.68 (s, 1H), 12.82 (br. s, 1H),11.70 (br. s, 1H), 8.55 (m, 3H), 8.00 (d, 1H), 7.92 (t, 1H), 7.59 (m,4H), 6.96 (m, 2H), 6.86 (m, 1H), 4.23 (s, 2H); MS 393.1 (M+H)⁺.

Example 167[2-(4-Cyanomethylphenylamino)-quinazolin-4-yl]-(4-fluoro-1H-indazol-3-yl)-amine(IIc-88):

Prepared in a manner similar to the above described Method A to afford awhite solid; ¹H NMR (DMSO) δ13.49 (s, 1H), 11.61 (br. s, 1H), 10.64 (br.s, 1H), 8.56 (d, 1H), 7.95 (t, 1H), 7.67 (d, 1H), 7.58 (t, 1H), 7.46 (t,1H), 7.43 (dd, 1H), 7.14 (m, 2H), 6.85 (dd, 3H), 3.88 (s, 2H); MS 410.1(M+H)⁺.

Example 168[2-(4-Cyanophenylamino)-quinazolin-4-yl]-(1H-indazol-3-yl)-amine(IIc-89):

Prepared in a manner similar to the above described Method A to afford awhite solid; ¹H NMR (DMSO) δ13.14 (s, 1H), 11.31 (br. s, 1H), 10.51 (br.s, 1H), 8.59 (d, 1H), 7.91 (t, 1H), 7.65 (d, 3H), 7.56 (t, 1H), 7.50 (m,2H), 7.45 (dd, 1H), 7.26 (d, 2H), 7.08 (t, 1H); MS 378.2 (M+H)⁺.

Example 169[2-(4-Cyanobenzylamino)-quinazolin-4-yl]-(1H-indazol-3-yl)-amine(IIc-90):

Prepared in a manner similar to the above described Method A to afford awhite solid; ¹H NMR (DMSO) δ13.12 (s, 1H), 12.91 (br. s, 1H), 11.60 (br.s, 1H), 8.57 (d, 1H), 7.91 (t, 1H), 7.63 (d, 1H), 7.55 (m,5H), 7.38 (t,1H), 6.89 (t, 1H), 6.84 (br. d, 2H), 4.19 (s, 2H); MS 392.2 (M+H)⁺.

Example 170(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-yloxy)-quinazolin-4-yl]-amine(IIb-1):

Prepared in a manner similar to the above described Method B to afford awhite solid, mp 327-328° C.; ¹H NMR (DMSO) δ-0.05-0.07 (2H, m),0.50-0.68 (2H, m), 1.28-1.40 (1H, m), 5.68 (1H,s), 7.40-7.50 (2H, m),7.50-7.64 (3H, m), 7.70-7.80 (2H, m), 7.82-8.08 (3H, m), 8.64 (1H,d),10.58 (1H, s), 12.07 (1H, s); IR (solid) 1621, 1595, 1575, 1554, 1508,1480, 1410, 1385, 1320, 1254, 1240, 1212, 1166, 830, 819, 758; MS 394.4(M+H)⁺

Example 171(5-Methyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-yloxy)quinazolin-4-yl]-amine(IIb-2):

Prepared in a manner similar to the above described Method B to afford apale brown solid, mp >300° C.; ¹H NMR (DMSO) δ1.62 (3H, s), 5.65 (1H,s), 7.96 (2H, br s), 7.55 (3H, d), 7.76 (2H, m), 7.92 (1H, d), 8.00 (2H,m), 8.58 (1H, d), 10.56 (1H, s), 11.99 (1H, s); IR (solid) 1625, 1601,1571, 1556, 1479, 1377, 1315, 1250, 1236, 1210, 1159; MS 368.7 (M+H)⁺

Example 172 (5-Methyl-2H-pyrazol-3-yl)-(2-phenoxy-quinazolin-4-yl)-amine(IIb-3):

Prepared in a manner similar to the above described Method B to afford atan solid, mp 287-290° C.; ¹H NMR (DMSO) δ2.10 (3H, s), 5.92 (1H, s),7.23 (2H, d), 7.29 (1H, t), 7.38 (1H, t), 7.46-7.53 (3H, m), 7.85 (1H,t), 8.58 (1H, d), 10.55 (1H, s), 12.11 (1H, s); IR (solid) 1622, 1602,1572, 1556, 1542, 1477, 1454, 1402, 1373, 1316, 1249, 1200, 1172, 1158;MS 318.3 (M+H)⁺

Example 173(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(5,6,7,8-tetrahydronaphthalen-2-yloxy)-quinazolin-4-yl]-amine(IIb-4):

Prepared in a manner similar to the above described Method B to afford asolid, mp 277-279° C.; ¹H NMR (DMSO) δ0.40-0.50 (2H, m), 0.89-0.96 (2H,m), 1.71-1.87 (5H, m), 2.70-2.83 (4H, m), 5.88 (1H, s), 6.88-6.96 (2H,m), 7.12 (1H, d), 7.39 (1H,t), 7.58 (1H, d), 7.76 (1H, t), 8.58 (1H, d),10.54 (1H, s), 12.20 (1H, s); IR (solid) 1731, 1641, 1614, 1570, 1506,1495, 1464, 1424, 1362, 1340, 1240, 880, 831, 812, 776, 758; MS 398.4(M+H)⁺

Example 174(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methylphenoxy)-quinazolin-4-yl]-amine(IIb-5):

Prepared in a manner similar to the above described Method B to affordan off-white solid, mp 283-284° C.; ¹H NMR (DMSO) δ0.49-0.53 (2H, m),0.89-0.96 (2H, m), 1.72-1.81 (1H, m), 2.40 (3H, s), 5.82 (1H, s), 7.03(1H, d), 7.08 (1H, s), 7.15 (1H, d), 7.35-7.46 (2H, m), 7.58 (1H, d),7.78 (1H, t), 8.62 (1H, d), 10.58 (1H, s), 12.25 (1H, s); IR (solid)1622, 1604, 1576, 1557, 1483, 1419, 1381, 1319, 1253, 1189, 1158, 997,842, 789, 763; MS 358.4 (M+H)⁺

Example 175[2-(3-Methoxyphenoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIb-6):

Prepared in a manner similar to the above described Method B to afford awhite solid, mp 277-278° C.; ¹H NMR (DMSO) δ2.15 (3H, s), 3.78 (3H, s),6.00 (1H, s), 6.77-6.90 (3H, m), 7.30-7.41 (2H, m), 7.52 (1H, d), 7.70(1H, t), 8.59 (1H, d), 10.57 (1H, s), 12.10 (1H, s); IR (solid) 1623,1603, 1575, 1556, 1487, 1456, 1430, 1373, 1316, 1253, 1192, 1142, 1046,1022, 833, 760; MS 348.4 (M+H)⁺

Example 176[2-(3,4-Dimethoxyphenoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIb-7):

Prepared in a manner similar to the above described Method B to affordan off-white solid, mp 277-278° C.; ¹H NMR (DMSO) δ2.09 (3H, s), 3.70(3H, s), 3.78 (3H, s), 5.98 (1H, s), 6.73-6.77 (1H, m), 6.90 (1H, s),7.00 (1H, d), 7.35-7.45 (1H, m), 7.58 (1H, d), 7.70-7.78 (1H, m), 8.63(1H, d), 10.55 (1H, s), 12.19 (1H, s).; IR (solid) 1626, 1603, 1576,1557, 1509, 1481, 1436, 1409, 1382, 1372, 1318, 1249, 1227, 1195, 1180,1158, 1120, 1029, 965, 835, 803, 767, 753; MS 378.4 (M+H)⁺

Example 177[2-(Benzo[1,3]dioxol-5-yloxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIb-8):

Prepared in a manner similar to the above described Method B to affordan off-white solid, mp 296-299° C. (dec.); ¹H NMR (DMSO) δ2.13 (3H, s),6.05 (1H, s), 6.09 (2H, s), 6.69 (1H, d), 6.90 (1H, s), 6.98 (1H, d),7.39 (1H, t), 7.53 (1H, d), 7.70 (1H,t), 8.58 (1H, d), 10.59 (1H, s); IR(solid) 1602, 1577, 1538, 1508, 1499, 1481, 1455, 1401, 1377, 1323,1251, 1241, 1169, 1121, 1038, 1022, 951, 935, 863, 813, 752; MS 362.4(M+H)⁺

Example 178[2-(3-Methoxycarbonylphenoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIb-9):

Prepared in a manner similar to the above described Method B to affordan off-white solid, mp 269-270° C.; ¹H NMR (DMSO) δ2.05 (3H, s), 3.90(3H, s), 5.88 (1H, s), 7.00-7.90 (7H, m), 8.50-8.65 (1H, m), 10.65 (1H,s); IR (solid) 1722, 1626, 1605, 1578, 1559, 1507, 1429, 1378, 1317,1282, 1272, 1255, 1204, 1185, 1096, 1021, 990, 869, 841, 758; MS 362.4(M+H)⁺

Example 179(5-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenoxymethyl-quinazolin-4-yl)-amine(IId-1):

Prepared in a manner similar to the above described Method C to afford apale yellow solid, mp 265-267° C.; ¹H NMR (DMSO) δ0.67 (2H, m), 0.93(2H, m), 1.87 (1H, m), 5.19 (2H, s), 6.55 (1H, br s), 6.90-7.02 (3H, m),7.26-7.30 (2H, m), 7.54 (1H, m), 7.74-7.83 (2H, m), 8.61 (1H, m), 10.45(1H, br s), 12.18 (1H, br s); MS 358.4 (M+H)⁺

Example 180(2-Benzyloxymethyl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IId-2):

Prepared in a manner similar to the above described Method C to afford awhite solid, mp 211-213° C.; ¹H NMR (DMSO) δ0.65 (2H, m), 0.90 (2H, m),1.86 (1H, m), 4.63 (2H, s), 4.68 (1H, s), 6.71 (1H, s), 7.28-7.54 (6H,m), 7.76-7.81 (2H, m), 8.61 (1H, m), 10.41 (1H, s), 12.19 (1H, s); MS372.3 (M+H)⁺

Example 181(2-Benzyl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IId-3):

Prepared in a manner similar to the above described Method D to afford awhite solid, mp 219-221° C.; ¹H NMR (DMSO) δ0.66 (2H, m), 0.95 (2H, m),1.87 (1H, m), 4.11 (2H, s), 6.31 (1H, s), 7.20-7.50 (6H, m), 7.71-7.79(2H, m), 8.55 (1H, m), 10.27 (1H, s), 12.15 (1H, s); MS 342.7 (M+H)⁺

Example 182(5-Cyclopropyl-2H-pyrazol-3-yl)-(2-methyl-quinazolin-4-yl)-amine(IId-4):

Prepared in a manner similar to the above described Method C to afford awhite solid, mp 289-290° C.; ¹H NMR (DMSO) δ2.31 (3H, s), 2.71 (3H, s),6.73 (1H, s), 7.75 (2H, q), 8.04 (1H, t), 8.82 (1H, s), 11.94 (1H, s),12.65 (1H, s); IR (solid) 3266, 1636, 1607, 1579, 1479, 1407, 769, 668;MS 240.4 (M+H)⁺

Example 183[2-(4-Chlorophenoxymethyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IId-5):

Prepared in a manner similar to the above described Method C to afford awhite solid; ¹H NMR (DMSO) δ1.58 (2H, m), 1.68 (2H, m), 1.85 (2H, m),2.20 (3H, s), 2.90 (2H, m), 3.00 (2H, m), 5.26 (2H, s), 6.15 (1H, s),7.15 (2H, d), 7.40 (2H, d), 10.25 (1H, br); MS 384.3 (M+H)⁺.

Example 184[2-(4-Chlorophenoxymethyl)-5,6,7,8-tetrahydro-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IId-6):

Prepared in a manner similar to the above described Method C to afford awhite solid; ¹H NMR (DMSO) δ1.80 (4H, m), 2.15 (3H, s), 2.55 (2H, mobscured), 2.75 (2H, m), 5.25 (2H, s), 6.12 (1H, s), 7.08 (2H, d), 7.35(2H, d), 9.80 (1H, br); MS 370.2 (M+H)⁺.

Example 185(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphtalen-2-ylsulfanyl)-6-phenylpyrimidin-4-yl]-amine(IIIa-1):

Prepared in a manner similar to the above described Method L to afford awhite solid, mp 233-234° C.; ¹H NMR (DMSO) δ0.21 (2H, br s), 0.56 (2H,br s), 1.17 (1H, br m), 5.35 (1H, br s), 7.02 (1H, br s), 7.49 (3H, m),7.59 (2H, m), 7.73 (1H, d), 7.88 (2H, m), 8.02 (3H, m), 8.30 (1H, m),10.01 (1H, s), 11.75 (1H, br s); IR (solid); MS 436.7(M+H)⁺

Example 186(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxycarbonyl-phenylylsulfanyl)-6-phenylpyrimidin-4-yl]-amine(IIIa-2):

Prepared in a manner similar to the above described Method L to afford awhite solid, mp 126-129° C.; ¹H NMR (DMSO) δ0.52 (2H, m), 0.87 (2H, m),1.69 (1H, m), 3.87 (3H, s), 5.47 (1H, s), 7.03 (1H, br s), 7.49 (3H, m),7.67 (1H, m), 7.87 (2H, m), 7.94 (1H, m), 8.09 (1H, m), 8.23 (1H, m),10.07 (1H, s), 11.94 (1H, s); IR (solid); MS 444.7(M+H)⁺

Example 187(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-amine(IIIa-3):

Prepared in a manner similar to the above described Method L to afford awhite solid, mp 248-250° C.; ¹H NMR (DMSO) δ0.21 (2H, br s), 0.55 (2H,br s), 0.94 (1H, br m), 5.31 (1H, br s), 6.55 (1H, br s), 7.57-7.66 (3H,m), 7.99-8.03 (4H, m), 8.25 (1H, s), 9.94 (1H, s), 11.75 (1H, br s); IR(solid); MS 360.7(M+H)⁺

Example 188(5-Cyclopropyl-2H-pyrazol-3-yl)-[5,6-dimethyl-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-amine(IIIa-4):

Prepared in a manner similar to the above described Method L to afford awhite solid, mp >270° C.; ¹H NMR (DMSO) δ0.14 (2H, d), 0.45 (2H, d),0.78 (1H, s), 2.05 (3H, s), 2.27 (3H, S), 5.26 (1H, S), 7.60 (3H, d),7.99 (3H, d), 8.21 (1H, s), 8.66 (1H, s), 11.60 (1H, s); IR (solid)1560, 1508, 1478, 1288, 1176, 1109, 994, 809, 740, 669; MS 388.7(M+H)⁺

Example 189(5-Cyclopropyl-2H-pyrazol-3-yl)-[5-methyl-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-amine(IIIa-5):

Prepared in a manner similar to the above described Method L to afford awhite solid, mp 197° C.; ¹H NMR (DMSO) δ0.21 (2H, d), 0.51 (2H, d), 0.78(1H, s), 2.08 (3H, s), 5.40 (1H, S), 7.57 (2H, d), 7.62 (1H, d), 7.92(1H, s), 7.97 (3H, d), 8.22 (1H, s), 8.88 (1H, s), 11.70 (1H, s); IR(solid) 1738, 1583, 1563, 1488, 1460, 1364, 1234, 1216, 808, 656; MS374.2(M+H)⁺

Example 190(5-Cyclopropyl-2H-pyrazol-3-yl)-[6-methyl-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-amine(IIIa-6):

Prepared in a manner similar to the above described Method L to afford awhite solid, mp 232° C.; ¹H NMR (DMSO) δ0.15 (2H, s), 0.51 (2H, s), 0.92(1H, s), 2.20 (3H, s), 5.22 (1H, s), 7.60 (2H, s), 7.67 (1H, d), 7.98(3H, s), 8.24 (1H, s), 9.79 (1H, s), 11.60 (1H, s); IR (solid) 1586,1508.7, 1485, 1282, 1180, 815, 788, 744, 674, 666; MS 374.2(M+H)⁺

Example 191(5-Cyclopropyl-2H-pyrazol-3-yl)-[6-(morpholin-4-yl)-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-amine(IIIa-7):

To a solution of 2,4,6-trichloropyrimidine (600 mg, 3.27 mmol) and3-amino-5-cyclopropylpyrazole (403 mg, 3.27 mmol) in EtOH (10 mL) wasadded triethylamine (456 μL, 3.27 mmol) and the reaction mixture wasstirred for 15 hours at room temperature. The solvent was evaporated andthe residue was purified by flash chromatography (SiO₂, Hexane/AcOEtgradient) to afford(5-cyclopropyl-2H-pyrazol-3-yl)-(2,6-dichloropyrimidin-4-yl)-amine (705mg, 80%).

To a solution of(5-cyclopropyl-2H-pyrazol-3-yl)-(2,6-dichloropyrimidin-4-yl)-amine (211mg, 0.781 mmol) and 2-naphthalenethiol (125 mg, 0.781 mmol) intert-butanol (5 mL) was added triethylamine (174 μL, 1.25 mmol) and theresulting mixture was heated at reflux for 15 hours. The reactionmixture was cooled to room temperature and partitioned between ethylacetate and aqueous NaHCO₃. The organic layer was washed with brine,dried over MgSO₄ and concentrated in vacuo. The residue was purified byflash chromatography (SiO₂, Hexane/AcOEt gradient) to afford[6-chloro-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.

The above formed[6-chloro-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(70 mg, 1.78.10⁻⁴ mol) was dissolved in morpholine (3 mL) and themixture heated at 120° C. for 15 hours. The solvent was evaporated andthe residue was purified by flash chromatography to afford IIIa-7 (50mg, 63%) as a white solid, mp 118-120° C.; ¹H NMR (DMSO) δ0.34-0.91 (4H,4×m), 1.28 and 1.78 (1H, 2×m), 3.32 (2H, m), 3.60 (6H, m), 5.38-6.16(2H, br m), 7.55-7.66 (3H, m), 7.95-8.02 (3H, m), 8.19 and 8.23 (1H,2×s), 9.28 and 9.31 (1H, 2×br s), 11.71 and 11.84 (1H, 2×br s); IR(solid); MS 445.2(M+H)⁺

Example 192(5-Cyclopropyl-2H-pyrazol-3-yl)-[6-(1-methylpiperazin-4-yl)-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-amine(IIIa-8):

Prepared in a manner substantially similar to the method describe abovefor compound IIIb-7 to afford a white solid, mp 113-115° C.; ¹H NMR(DMSO) δ0.35-0.91 (4H, 4×m), 1.31 and 1.78 (1H, 2×m), 2.17 and 2.19 (3H,2×s), 2.29 (4H, m), 3.35 (2H, m), 3.61 (2H, m), 5.38-6.20 (2H, br m),7.55-7.66 (3H, m), 7.95-8.02 (3H, m), 8.17 and 8.23 (1H, 2×s), 9.26 and9.32 (1H, 2×br s), 11.71 and 11.85 (1H, 2×br s); IR (solid); MS458.3(M+H)⁺

Example 193[6-(2,6-Dimethylphenyl)-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-9):

Prepared in a manner similar to the above described Method L to affordan off-white solid, mp 148-152° C.; ¹H NMR (DMSO) δ2.10 (6H, s), 2.26(3H, d), 5.09 and 6.31 (1H, 2×br s), 7.03 (3H, s), 7.22 (1H, s), 7.59(2H, t), 7.69 (1H, d), 7.99 (3H, d), 8.28 (1H, s), 9.93 (1H, s), 11.67(1H, br s); IR (solid) 2970, 1739, 1436, 1365, 1229, 1217, 1205; MS438.3(M+H)⁺

Example 194[6-(2-Methylphenyl)-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-10):

Prepared in a manner similar to the above described Method L to afford awhite solid, mp 211-214° C.; ¹H NMR (DMSO) δ1.41 (3H, s), 2.30 (3H, s),5.26 and 6.55 (1H, 2×br s), 7.34 (5H, m), 7.62 (2H, t), 7.70 (1H, d),7.99 (3H, t), 8.30 (1H, s), 9.97 (1H, s), 11.73 (1H, br s); IR (solid)2356, 1615, 1582, 1483, 1265, 851, 822, 761; MS 424.0(M+H)⁺

Example 195[2-(4-Acetamido-phenylsulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-11):

Prepared in a manner similar to the above described Method L to afford awhite solid, mp 153-155° C.; ¹H NMR (DMSO) δ2.01 (3H, s), 2.08 (3H, s),5.43 (1H, s), 6.96 (1H, br s), 7.49-7.88 (9H, m), 10.00 (1H, br s),10.23 (1H, s), 11.86 (1H, br s); MS 417.2(M+H)⁺

Example 196(5-Methyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-ylsulfanyl)-6-phenyl-pyrimidin-4-yl]-amine(IIIa-12):

Prepared in a manner similar to the above described Method L to afford awhite solid, mp 237-239° C.; ¹H NMR (DMSO) δ1.39 (3H, br s), 5.12 (1H,br s), 6.98 (1H, br s), 7.50 (3H, m), 7.62-7.63 (2H, m), 7.72 (1H, d),7.90 (2H, m), 8.03-8.05 (3H, m), 8.31 (1H, s), 10.00 (1H, s), 11.73 (1H,br s); IR (solid); MS 410.2(M+H)⁺

Example 197[2-(4-Isobutyrylylamino-phenylsulfanyl)-6-phenylpyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-13):

Prepared in a manner similar to the above described Method L to affordan off-white solid, mp 201-202° C.; ¹H NMR (DMSO) δ1.05-1.13 (6H, m),1.97 (3H, s), 2.65 (1H, m), 5.37 (1H, br s), 6.93 (1H, br s), 7.50-7.58(5H, m), 7.78-7.90 (4H, m), 9.99, 10.12 and 11.84 (3H, 3 ×br s); IR(solid) 1676, 1614, 1586, 1573, 1514, 1483, 1395, 1299, 1262, 1242,1214, 1168, 1089, 988; MS 445.3 (M+H)⁺

Example 198[6-(4-Methylpiperazin-1-yl)-2-methylsulfanyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-14):

Prepared in a manner similar to the above described Method M to affordan off-white solid; ¹H NMR (DMSO) δ2.18 (3H, s), 2.20 (3H, s), 2.36 (4H,m), 2.41 (3H, s), 3.46 (4H, m), 5.91 (1H, s), 6.41 (1H, br s), 9.20 (1H,S), 11.87 (1H, s); IR (solid); MS 320.3(M+H)⁺

Example 199(5-Methyl-2H-pyrazol-3-yl)-[6-phenyl-2-(4-propionylamino-phenylsulfanyl)-pyrimidin-4-yl]-amine(IIIa-15):

Prepared in a manner similar to the above described Method L to afford apale pink solid, mp 204-206° C.; ¹H NMR (DMSO) δ1.09-1.13 (3H, m), 2.00(3H, s), 2.33-2.37 (2H, m), 5.40 (1H, br s), 6.95 (1H, br s), 7.50 (3H,m), 7.56-7.58 (2H, m), 7.76-7.78 (2H, m), 7.88 (2H, m), 9.99, 10.15 and11.85 (3H, 3×br s); IR (solid) 1678, 1623, 1580, 1534, 1496, 1453, 1398,1307, 1245, 1203, 1119, 1049, 1030, 1004; MS 431.2(M+H)⁺

Example 200[2-(4-Cyclopropanecarbonylamino-phenylsulfanyl)-6-phenylpyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-16):

Prepared in a manner similar to the above described Method L to affordan off-white solid, mp 253-255° C.; ¹H NMR (DMSO) δ0.82-0.83 (4H, m),1.83 (1H, m), 2.00 (3H, s), 5.41 (1H, br s), 6.88 (1H, br s), 7.42-7.50(3H, m), 7.56-7.58 (2H, m), 7.76-7.78 (2H, m), 7.89 (2H, m), 9.99, 10.47and 11.85 (3H, 3×br s); IR (solid) 1672, 1621, 1591, 1581, 1573, 1537,1495, 1448, 1405, 1390, 1312, 1254, 1246, 1202, 1192, 1179, 1119.2,1005, 959; MS 443.2(M+H)⁺

Example 201(5-Methyl-2H-pyrazol-3-yl)-{6-phenyl-2-[4-(propane-1-sulfonylamino)-phenylsulfanyl]-pyrimidin-4-yl}-amine(IIIa-17):

Prepared in a manner similar to the above described Method L to affordan off-white solid, mp 232-235° C.; ¹H NMR (DMSO) δ0.94 (3H, t), 1.71(2H, m), 2.12 (3H,s), 3.13 (2H, t), 5.59 (1H, s), 7.31 (2H, d), 7.49(3H, s), 7.59 (2H, d), 7.85 (2H, s), 10.00 (1H, br s), 10.16 (1H, s),12.05 (1H, br s); IR (solid) 1628, 1587, 1545, 1525, 1496, 1455, 1311,1255, 1236, 1212, 1186, 1140, 1032, 1001, 934; MS 481.2(M+H)⁺

Example 202[2-(4-Ethanesulfonylamino-phenylsulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-18):

Prepared in a manner similar to the above described Method L to afford apale yellow solid, mp 251-254° C.; ¹H NMR (DMSO) δ1.21 (3H, t), 2.12(3H,s), 3.15 (2H, q), 5.59 (1H, s), 7.32 (2H, d), 7.49 (3H, s), 7.57(2H, d), 7.85 (2H, s), 9.99 (1H, br s), 10.15 (1H, br s), 11.90 (1H, brs); IR (solid) 1621, 1585, 1542, 1523, 1495, 1455, 1315, 1257, 1208,1142, 1049, 1033, 1002, 932; MS 467.2(M+H)⁺

Example 203[2-(4-Acetamidophenyl-sulfanyl)-6-(2-methylphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-19):

Prepared in a manner similar to the above described Method L to afford awhite solid, mp 212-214° C.; ¹H NMR (DMSO) δ2.01 (3H, s), 2.08 (3H, s),2.24 (3H, s), 5.43 (1H, s), 6.56 (1H, br s), 7.49-7.88 (9H, m), 10.00(1H, br s), 10.23 (1H, s), 11.86 (1H, br s); IR (solid1701, 1634, 1588,1555, 1496, 1390, 1307, 1208, 1169, 823, 803; MS 431.4(M+H)⁺

Example 204[2-(4-Isobutanecarbonylamino-phenyl-sulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-20):

Prepared in a manner similar to the above described Method L to affordan off-white solid, mp 241-243° C.; ¹H NMR (DMSO) δ0.95-0.96 (6H, m),2.00 (3H, s), 2.11 (1H, m), 2.23-2.25 (2H, m), 5.43 (1H, br s), 6.95(1H, br s), 7.50-7.58 (5H, m), 7.77-7.89 (4H, m), 10.00, 10.13 and 11.84(3H, 3×br s); IR (solid) 1660, 1628, 1589, 1575, 1543, 1525, 1496, 1451,1398, 1357, 1314, 1301, 1251, 1206, 1108, 995; MS 459.2 (M+H)⁺

Example 205[2-(4-Acetamido-phenyl-sulfanyl)-5-methyl-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-21):

Prepared in a manner similar to the above described Method L to afford apale pink solid, mp 276-277° C.; ¹H NMR (DMSO) δ1.98 (3H, s), 2.08 (6H,s), 5.41 (1H, br s), 7.47-7.55 (7H, m), 7.72-7.74 (2H, m), 8.89, 10.20and 11.87 (3H, 3×br s); IR (solid) 1676, 1591, 1555, 1540, 1519, 1493,1393, 1375, 1303, 1260, 1230, 1176, 1148, 1045, 1011, 969; MS 431.2(M+H)⁺

Example 206[2-(4-Acetamido-phenyl-sulfanyl)-6-(4-ethoxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-22):

Prepared in a manner similar to the above described Method L to affordan off white solid, mp 241-245° C.; ¹H NMR (DMSO) δ1.99 (3H,s), 2.06(3H, s), 3.82 (3H, s), 5.44 (1H, s), 7.03 (2H, d), 7.53 (2H, d), 7.71(2H, s), 7.83 (2H, s), 10.12 (1H, s), 10.23 (1H, s), 11.84 (1H, s); IR(solid) 1627, 1606, 1571, 1511, 1313, 1257, 1181, 830; MS 447.2 (M+H)⁺

Example 207[6-(3-Acetamidophenyl)-2-(4-acetamido-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-23):

Prepared in a manner similar to the above described Method L to afford abrown solid, mp 227-230° C.; ¹H NMR (DMSO) δ2.01 (3H, s), 2.11 (6H, s),5.34 (1H, s), 6.99 (1H, br s), 7.41 (1H, t), 7.49-7.62 (3H, m),3.71-3.76 (3H, m), 8.19 (1H s), 10.09-10.18 (2H, br s), 10.23 (1H, s),12.20 (1H, br s); IR (solid) 1635, 1573, 1533, 1488, 1372, 1318, 1297,827, 798; MS 474.3 (M+H)⁺

Example 208[2-(4-Isopropanesulfonylamino-phenyl-sulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-24):

Prepared in a manner similar to the above described Method L to afford awhite solid, mp 255-257° C.; ¹H NMR (DMSO) δ1.28 (6H, d), 2.14 (3H,s),3.32 (1H, s), 5.60 (1H, s), 7.36 (2H, d), 7.49 (3H, s), 7.60 (2H, d),7.85 (2H, s), 10.00 (1H, br s), 10.11 (1H, s), 11.92 (1H, br s); IR(solid) 1625, 1587, 1574, 1545, 1525, 1495, 1313, 1295, 1257, 1234,1136, 1000, 934; MS 481.2 (M+H)⁺

Example 209{2-[4-(2-Dimethylamino-acetylamino)-phenylsulfanyl]-6-phenyl-pyrimidin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-25):

Prepared in a manner similar to the above described Method L to affordan off-white solid, mp 213-215° C.; ¹H NMR (DMSO) δ2.00 (3H, s), 2.31(6H, s), 3.15 (2H, s), 5.45 (1H, s), 6.83 (1H, br s), 7.46-7.51 (3H, m),7.59 (2H, d), 7.80-7.92 (5H, m), 9.98 (1H, s), 10.05 (1H, s); IR (solid)1701, 1617, 1587, 1571, 1509, 1480, 1456, 1304, 1284, 1254, 1238, 1213,1181, 1156, 987, 833, 782, 754, 695; MS 460.3(M+H)⁺

Example 210[2-(3-Chloro-benzylsulfanyl)-6-morpholin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-26):

Prepared in a manner similar to the above described Method M to afford awhite solid, mp 224-225° C.; ¹H NMR (DMSO) δ2.17 (3H, s), 3.40-3.50 (4H,m), 3.60-3.71 (4H, m), 4.30 (2H, s), 5.95 (1H, brs), 6.41 (1H, brs),7.23-7.55 (4H, m), 9.31 (1H, s), 11.89 (1H, brs); IR (solid) 1557, 1476,1442, 1401, 1314, 1232, 1121, 1018; MS 417.4 (M+H)⁺

Example 211[2-(3-Chloro-benzylsulfanyl)-6-(2-methoxy-ethylamino)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-27):

Prepared in a manner similar to the above described Method M to afford awhite solid, mp 101-102° C.; ¹H NMR (DMSO) δ2.15 (3H, s), 3.21 (3H, s),3.28-3.41 (4H, m), 4.29 (2H, s), 5.78 (1H, brs), 6.20 (1H, brs), 7.10(1H, brs), 7.21-7.50 (4H, m), 9.01 (1H, brs); IR (solid) 1598, 1555,1527, 1336, 1293, 1117, 1079, 974, 783; MS 405.4 (M+H)⁺

Example 212[2-Benzylsulfanyl-6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-28):

Prepared in a manner similar to the above described Method M to afford ayellow gum; ¹H NMR (CDCl₃) δ2.23 (3H, s), 2.28 (3H, s), 2.31-2.64 (4H,m), 3.30-3.65 (4H, m), 4.38 (2H, s), 5.83 (1H, s), 6.23 (1H, br s),7.17-7.49 (5H, m), 7.98-8.18 (1H, m); IR (solid) 1555, 1494, 1371, 1315,1286, 1233, 999, 977, 801, 774, 709; MS 396.4 (M+H)⁺

Example 213[2-Benzylsulfanyl-6-morpholin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-29):

Prepared in a manner similar to the above described Method M to affordan off-white foam; ¹H NMR (CDCl₃) δ2.31 (3H, s), 3.39-3.80 (8H, m), 4.39(2H, s), 5.84 (1H, s), 6.25 (1H, brs), 7.20-7.50 (5H, m), 8.10 (1H, s);IR (solid) 1557, 1486, 1442, 1314, 1229, 1213, 1121, 767, 698; MS 383.4(M+H)⁺

Example 214[2-(3-Chloro-benzylsulfanyl)-6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-30):

Prepared in a manner similar to the above described Method M to afford awhite foam; ¹H NMR (CDCl₃) δ2.31 (3H, s), 2.35 (3H, s), 2.40-2.51 (4H,m), 3.56-3.69 (4H, m), 4.34 (2H, s), 5.85 (1H, s), 6.29 (1H, brs), 6.89(1H, s), 7.18-7.50 (4H, m); IR (solid) 1553, 1514, 1484, 1446, 1277,1228, 999, 799; MS 430.4 (M+H)⁺

Example 215[2-(4-methoxy-benzylsulfanyl)-6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-31):

Prepared in a manner similar to the above described Method M to afford ayellow oil; ¹H NMR (CDCl₃) δ2.28 (3H, s), 2.33 (3H, s), 2.44-2.45 (4H,m), 3.62 (4H, m), 3.80 (3H, s), 4.34 (2H, s), 5.32 (1H, s), 6.28 (1H, brs), 6.83-6.85 (2 H, m), 7.34-7.36 (2H, m); IR (solid) 1659, 1554, 1508,1485, 1449, 1366, 1318, 1302, 1277, 1230, 1166, 1146, 1030, 999, 973,948; MS 443.4 (M+H)⁺

Example 216[2-(4-Acetamido-phenyl-sulfanyl)-6-tert-butyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-32):

Prepared in a manner similar to the above described Method L to afford awhite solid, mp 227-228° C.; ¹H NMR (DMSO) δ1.10 (3H, br s), 1.20 (9H,s), 2.00 (3H, s), 2.35 (2H, q), 5.35 (1H, br s), 6.55 (1H, br s), 7.55(2H, d), 7.75 (2H, d), 10.1 (1H, br s), 1.15 (1H, s), 12.1 (1H, br s);IR (solid); MS (M+H)⁺

Example 217(5-Cyclopropyl-2H-pyrazol-3-yl)-[6-phenyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-amine(IIIa-33):

Prepared in a manner similar to the above described Method L to affordan off-white solid, mp 208-209° C.; ¹H NMR (DMSO) δ0.52 (2H, m), 0.80(2H, m), 1.08-1.10 (3H, m), 1.65 (1H, br s), 2.33-2.37 (2H, m), 5.50(1H, br s), 7.03 (1H, br s), 7.47 (3H, m), 7.50-7.58 (2H, m), 7.76-7.77(2H, m), 7.88-7.98 (2H, m), 10.00, 10.11 and 11.86 (3H, 3×br s); IR(solid) 1676, 1617, 1575, 1539, 1520, 1485, 1459, 1418, 1395, 1304,1255, 1243, 1215, 1161, 1071, 990; MS 457.4 (M+H)⁺

Example 218[2-(3-Chloro-benzylsulfanyl)-6-(piperidin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-34):

Prepared in a manner similar to the above described Method M to afford awhite solid, mp 234-235° C.; ¹H NMR (DMSO) δ1.40-1.64 (6H, m), 2.13 (3H,s), 3.42-3.51 (4H, m), 4.27 (2H, s), 5.85 (1H, br s), 6.46 (1H, brs),7.23-7.41 (3H, m), 7.48 (1H, s), 9.18 (1H, s), 11.83 (1H, s); IR (solid)1598, 1546, 1483, 1398, 1317, 1227, 974, 798, 779; MS 415.4 (M+H)⁺

Example 219(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(morpholinesulfonyl)-benzylsulfanyl]-6-morpholin-4-yl-pyrimidin-4-yl}-amine(IIIa-35):

Prepared in a manner similar to the above described Method M to afford awhite solid; ¹H NMR (DMSO) δ2.24 (3H, s), 2.90-3.01 (4H, m), 3.29-3.36(4H, m), 3.48-3.57 (4H, m), 3.67-3.75 (4H, m), 4.43 (2H, s), 5.82-6.10(2H, m), 7.50-7.70 (5H, m); IR (solid) 1550, 1483, 1441, 1346, 1308,1255, 1160, 1112, 941, 726; MS 532.5 (M+H)⁺

Example 220{6-(2-Methoxy-ethylamino)-2-[4-(morpholinesulfonyl)-benzylsulfanyl]-pyrimidin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-36):

Prepared in a manner similar to the above described Method M to afford awhite solid, mp 193-195° C.; ¹H NMR (DMSO) δ2.15 (3H, s), 2.79-2.89 (4H,m), 3.34 (3H, s), 3.40-3.51 (4H, m), 3.59-3.67 (4H, m), 4.41 (2H, s),5.76-5.72 (1H, m), 6.20 (1H, brs), 7.10 (1H, brs), 7.61-7.74 (4H, m),9.03 (1H, brs), 11.81 (1H, brs); IR (solid) 1593, 1555, 1484, 1350,1298, 1255, 1160, 1107, 936; MS 520.5 (M+H)⁺

Example 221{6-(4-methylpiperazin-1-yl)-2-[4-(morpholinesulfonyl)-benzylsulfanyl]-pyrimidin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-37):

Prepared in a manner similar to the above described Method M to afford awhite solid, mp 206-207° C.; ¹H NMR (DMSO) δ2.09 (3H, s), 2.20 (3H, s),2.26-2.40 (4H, m), 2.78-2.88 (4H, m), 3.38-3.49 (4H, m), 3.56-3.67 (4H,m), 4.41 (2H, s), 5.82 (1H, brs), 6.42 (1H, brs), 7.60-7.74 (4H, m),9.26 (1H, s), 11.89 (1H, brs); IR (solid) 1583, 1558, 1479, 1346, 1231,1160, 1112, 998, 969, 926; MS 545.5 (M+H)⁺

Example 222[6-Methoxymethyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-38):

Prepared in a manner similar to the above described Method L to afford awhite solid; ¹H NMR (DMSO) δ1.03-1.14 (3H, m), 2.00 (3H, s), 2.29-2.40(2H, m), OMe under DMSO, 4.22 (2H, m), 5.26 (1H, brs), 6.45 (1H, brs),7.44-7.56 (2H, m), 7.68-7.80 (2H, m), 9.86 (1H, brs), 10.11 (1H, s),11.79 (1H, brs); IR (solid) 1670, 1593, 1517, 1479, 1393, 1360, 1269,1174, 1107; MS 399.4 (M+H)⁺

Example 223[2-(4-Methoxycarbonyl-phenyl-sulfanyl)-6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-39):

Prepared in a manner similar to the above described Method L to afford awhite solid, mp 204-205° C.; ¹H NMR (DMSO) δ1.89 (3H, brs), 3.85 (3H,s), OMe under DMSO, 4.23 (2H, s), 5.22 (1H, brs), 6.51 (1H, brs),7.70-7.81 (2H, m), 7.96-8.06 (2H, m), 9.99 (1H, brs), 11.85 (1H, brs);IR (solid) 1721, 1621, 1583, 1519, 1484, 1289, 1271, 1178, 1119, 1109,997, 841; MS 386.3 (M+H)⁺

Example 224[2-(3,5-Dimethoxy-benzylsulfanyl)-6-morpholin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-40):

Prepared in a manner similar to the above described Method M to afford awhite solid; ¹H NMR (DMSO) δ2.15 (3H, s), 3.40-3.49 (4H, m), 3.60-3.74(10H, m), 4.25 (2H, s), 5.88 (1H, brs), 6.31-6.61 (5H, m), 9.32 (1H, s),11.86 (1H, s); IR (solid) 1581, 1556, 1470, 1439, 1315, 1232, 1205,1159, 1144; MS 443.4 (M+H)⁺

Example 225[2-(3,5-Dimethoxy-benzylsulfanyl)-6-pyrrolidin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-41):

Prepared in a manner similar to the above described Method M to afford awhite solid; ¹H NMR (DMSO) δ1.80-1.97 (4H, m), 2.15 (3H, s), 3.43-3.45(4H, m), 3.69 (6H, s), 4.26 (2H, s), 5.85 (1H, brs), 6.18 (1H, brs),6.35 (1H, brs), 6.60 (2H, s), 9.12 (1H, s), 11.88 (1H, s); IR(solid1598, 1560, 1474, 1470, 1346, 1303, 1207, 1136, 1050; MS 427.4(M+H)⁺

Example 226(5-Methyl-2H-pyrazol-3-yl)-[6-morpholin-4-yl-2-(naphthalene-2-ylmethylsulfanyl)-pyrimidin-4-yl]-amine(IIIa-42):

Prepared in a manner similar to the above described Method M to affordan off-white solid; ¹H NMR (DMSO) δ2.15 (3H, s), 3.37-3.50 (4H, m),3.59-3.70 (4H, m), 4.48 (2H, s), 5.88 (1H, brs), 6.40 (1H, brs),7.40-7.60 (3H, m), 7.78-7.95 (4H, m), 9.30 (1H, s), 11.89 (1H, brs); IR(solid) 1607, 1555, 1484, 1441, 1398, 1365, 1308, 1231, 1179, 1112; MS433.4 (M+H)⁺

Example 227{2-(4-Acetamido-phenyl-sulfanyl)-6-[4-(3-dimethylamino-propoxy)-phenyl]-pyrimidin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-43):

Prepared in a manner similar to the above described Method N to afford awhite solid, mp 219-222° C.; ¹H NMR (CDCl₃) 67.1.97-2.07 (2H, m), 2.14(3H, s), 2.18 (3H, s), 2.30 (6H, s), 2.52 (2H, t), 4.09 (2H, t), 5.56(1H, s), 6.80 (1H, br s), 6.99 (2H, d), 7.60 (2H, d), 7.68-7.78 (3H, m),7.85 (2H, d); IR (solid) 1606, 1590, 1512, 1482, 1309, 1250, 1238, 1210,1178, 1151, 1055, 989, 824, 711, 690, 665, 656; MS 518.4 (M+H)⁺

Example 228[2-(4-Acetamidophenylsulfanyl)-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-44):

Prepared in a manner similar to the above described Method P to afford awhite solid; MS 426.4 (M+H)⁺

Example 229[6-Hydroxymethyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-45):

Prepared from IIIa-48 according to Method O to afford a white solid; ¹HNMR (DMSO) δ1.08-1.18 (3H, m), 1.96 (3H, brs), 2.29-2.40 (2H, m),4.20-4.40 (3H, m), 5.20-5.46 (2H, m), 6.56 (1H, s), 7.50 (2H, d), 7.79(2H, d), 9.90 (1H, brs), 10.13 (1H, s), 11.78 (1H, brs); MS 385.4 (M+H)⁺

Example 230[2-(4-Acetamido-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-46):

Prepared in a manner similar to the above described Method L to affordan off-white solid, mp 249-250° C.; ¹H NMR (DMSO) δ1.99 (3H, s), 2.08(3H, s), 5.38 (1H, br s), 6.45 (1H, br s), 7.50 (2H, d), 7.71 (2H, d),7.98 (1H, d), 9.89 (1H, br s), 10.19 (1H, br s), 11.83 (1H, br s); IR(solid) 1657, 1609, 1584, 1515, 1494, 1468, 1395, 1372, 1355, 1330,1316, 1201, 1175, 1157, 1027, 993; MS 341.4 (M+H)⁺

Example 231[6-(1-Butoxycarbonyl)-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-47):

Prepared in a manner similar to the above described Method L to afford ayellow solid, ¹H NMR (DMSO) δ0.90-0.98 (3H, m), 1.03-1.12 (3H, m),1.31-1.45 (2H, m), 1.60-1.71 (2H, m), 1.94 (3H, brs), 2.29-2.40 (2H, m),4.20-4.30 (2H, m), 5.25 (1H, brs), 7.08 (1H, brs), 7.49-7.55 (2H, m),7.72-7.81 (2H, m), 10.15 (1H, brs), 10.32 (1H, brs), 11.89 (1H, brs); IR(solid) 1736, 1679, 1622, 1584, 1517, 1489, 1284, 1174; MS 455.4 (M+H)⁺

Example 232[6-Methoxycarbonyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-48):

Prepared in a manner similar to the above described Method L to afford ayellow solid; ¹H NMR (DMSO) δ1.10 (3H, t), 1.94 (3H, brs), 2.35 (2H, q),3.84 (3H, s), 5.22 (1H, brs), 7.05 (1H, s), 7.52 (2H, d), 7.79 (2H, d),10.18 (1H, brs), 10.38 (1H, brs), 11.89 (1H, brs).; IR (solid) 1741,1679, 1617, 1589, 1512, 1484, 1374, 1284, 1250; MS 413.4 (M+H)⁺

Example 233(5-Methyl-2H-pyrazol-3-yl)-(6-phenyl-2-phenylamino-pyrimidin-4-yl)-amine(IIIc-1):

white solid; MS 343.4 (M+H)⁺

Example 234(5-Cyclopropyl-2H-pyrazol-3-yl)-(6-phenyl-2-phenylamino-pyrimidin-4-yl)-amine(IIIc-2):

white solid, mp 267-269° C.; ¹H NMR (DMSO) δ0.63 (2H, m), 0.96 (2H, m),1.87 (1H,m), 6.07 (1H, s), 6.84 (1H, br s), 7.20 (1H, m), 7.33-8.05 (9H,m), 10.52 (1H, br s), 11.08 (1H, br s), 12.53 (1H, br s); IR (solid); MS369.7 (M+H)⁺

Example 235(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methylphenylamino)-6-phenyl-pyrimidin-4-yl]-amine(IIIc-3):

white solid, mp 267-270° C.; ¹H NMR (DMSO) δ0.63 (2H, m), 0.94 (2H, m),1.87 (1H,m), 2.36 (3H, s), 6.12 (1H, s), 6.81 (1H, br s), 7.03 (1H, m),7.29-7.94 (8H, m), 10.43 (1H, br s), 11.12 (1H, br s), 12.47 (1H, br s);IR (solid); MS 383.7 (M+H)⁺

Example 236[2-(4-cyanomethylphenylamino)-6-phenyl-pyrimidin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIIc-4):

pale yellow solid, mp 294-297° C.; ¹H NMR (DMSO) δ0.64 (2H, m), 0.97(2H, m), 1.89 (1H, m), 4.06 (2H, s), 6.07 (1H, s), 6.87 (1H, br s), 7.40(2H, m), 7.63-7.90 (5H, m), 7.95 (2H, m), 10.51 (1H, br s), 11.02 (1H,br s), 12.57 (1H, br s); IR (solid); MS 408.8 (M+H)⁺

Example 237(5-Cyclopropyl-2H-pyrazol-3-yl)-[6-phenyl-2-(pyridin-3-ylmethylamino)-pyrimidin-4-yl]-amine(IIIc-5):

off-white solid, mp 191-193° C.; ¹H NMR (DMSO) δ0.65 (2H, m), 0.89 (2H,m), 1.83 (1H, m), 4.59 (2H, s), 6.04 (1H, br s), 6.76 (1H, br s),7.32-7.56 (5H, m), 7.77 (1H, m), 7.88-7.97 (2H, m), 8.43 (1H, m), 8.61(1H, s), 9.47 (1H, br s), 11.93 (1H, br s); IR (solid); MS 384.8 (M+H)⁺

Example 238[2-(3-Chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-6):

off-white solid; ¹H NMR (CD₃OD) δ5.95 (1H, s), 6.65 (1H, s), 6.90 (1H,d), 7.18 (1H, t), 7.32 (1H, d), 7.58 (1H, t), 7.82 (1H, s), 8.18 (1H,d), 8.25 (1H, d), 8.65 (1H, s); MS 422.1 (M+H)⁺

Example 239[2-(3-Chlorophenyl)amino-6-(3,4,5-trimethoxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-7):

white solid; MS 467.7 (M+H)⁺

Example 240(5-Methyl-2H-pyrazol-3-yl)-[2-(4-sulfamoylphenylamino)-6-(3,4,5-trimethoxyphenyl)-pyrimidin-4-yl]-amine(IIIc-8):

white solid; MS 512.6 (M+H)⁺

Example 241[2-(4-Chlorophenyl)amino-6-methyl-pyrimidin-4-yl]-[5-(furan-2-yl)-2H-pyrazol-3-yl]-amine(IIIc-9):

white solid; MS 367.1 (M+H)⁺

Example 242[2-(Benzimidazol-2-ylamino-)6-ethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-10):

MS 335.5 (M+H)⁺

Example 243[2-(4-Chlorophenyl)amino-6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(IIIc-11):

MS 377.5 (M+H)⁺

Example 244[2-(4-Chlorophenyl)amino-6-ethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-12):

MS 329.4 (M+H)⁺

Example 245(5-tert-Butyl-2H-pyrazol-3-yl)-[2-(3-chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yl]-amine(IIIc-13):

off-white solid; ¹H NMR (CD₃OD) δ1.32 (9H, s), 6.18 (1H, s), 7.04 (1H,s), 7.14 (1H, d), 7.35 (1H, t), 7.58 (1H, d), 7.82 (1H, t), 7.91 (1H,s), 8.35 (1H, d), 8.40 (1H, d), 8.90 (1H, s); MS 464.2 (M+H)⁺

Example 246[2-(3-Chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(IIIc-14):

δ off-white solid; ¹H NMR (CD₃OD) δ6.66 (1H, s), 7.12 (1H, d), 7.30-7.45(5H, m), 7.50 (1H, d), 7.62 (2H, d), 7.78 (1H, t), 7.88 (1H, s), 8.35(1H, d), 8.42 (1H, d), 8.85 (1H, s); MS 484.1 (M+H)⁺

Example 247[5-(Furan-2-yl)-2H-pyrazol-3-yl]-(6-phenyl-2-phenylamino-pyrimidin-4-yl)-amine(IIIc-15):

MS 395.4 (M+H)⁺

Example 248[2-(Benzimidazol-2-ylamino)-6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(IIIc-16):

MS 383.2 (M+H)⁺

Example 249[2-(Benzimidazol-2-ylamino)-6-methyl-pyrimidin-4-yl]-[5-(Furan-2-yl)-2H-pyrazol-3-yl]-amine(IIIc-17):

MS 373.4 (M+H)⁺

Example 250[2-(4-Chlorophenylamino)-6-methyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-18):

MS 315.4 (M+H)⁺

Example 251[2-(4-Chlorophenyl)amino-5,6-dimethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-19):

MS 329.4 (M+H)⁺

Example 252(5,6-Dimethyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-20):

MS 295.5 (M+H)⁺

Example 253[2-(4-Chlorophenyl)amino-6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-21):

MS 345.1 (M+H)⁺

Example 254[2-(Benzimidazol-2-ylamino)-6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-22):

MS 351.2 (M+H)⁺

Example 255(6-Methoxymethyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-23):

MS 311.2 (M+H)⁺

Example 256(6-Methyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-24):

MS 281.1 (M+H)⁺

Example 257[2-(2-Chlorophenoxymethyl)-6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(IIId-1):

MS 392.1 (M+H)⁺

Example 258[2-(2-Chlorophenoxymethyl)-6-methyl-pyrimidin-4-yl]-[5-(furan-2-yl)-2H-pyrazol-3-yl]-amine(IIId-2):

MS 382.1 (M+H)⁺

Example 259(6-methyl-2-phenoxymethyl-pyrimidin-4-yl)-(5-phenyl-2H-pyrazol-3-yl)-amine(IIId-3):

MS 358.2 (M+H)⁺

Example 260[5-(Furan-2-yl)-2H-pyrazol-3-yl]-(6-methyl-2-phenoxymethyl-pyrimidin-4-yl)-amine(IIId-4):

MS 348.2 (M+H)⁺

Example 261[5-(Furan-2-yl)-2H-pyrazol-3-yl]-(6-methyl-2-phenylsulfanylmethyl-pyrimidin-4-yl)-amine(IIId-5):

MS 364.1 (M+H)⁺

Example 262[6-Methyl-2-(4-methyl-phenylsulfanylmethyl)-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(IIId-6):

MS 388.1 (M+H)⁺

Example 263[5-(Furan-2-yl)-2H-pyrazol-3-yl]-[6-Methyl-2-(4-methyl-phenylsulfanylmethyl)-pyrimidin-4-yl]-amine(IIId-7):

MS 378.1 (M+H)⁺

Example 264[2-(4-Fluoro-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(IIId-8):

MS 376.2 (M+H)⁺

Example 265[2-(4-Fluoro-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-[5-(furan-2-yl)-2H-pyrazol-3-yl]-amine(IIId-9):

MS 366.2 (M+H)⁺

Example 266(6-Ethyl-2-phenylsulfanylmethyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIId-10):

MS 326.2 (M+H)⁺

Example 267(6-Ethyl-2-phenoxymethyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIId-11):

MS 310.2 (M+H)⁺

Example 268[6-Ethyl-2-(4-fluorophenoxymethyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIId-12):

MS 328.2 (M+H)⁺

Example 269[6-Ethyl-2-(1-methyl-1-phenyl-ethyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIId-13):

MS 322.2 (M+H)⁺

Example 270[2-(4-Chlororophenoxymethyl)-6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(IIId-14):

MS 392.2 (M+H)⁺

Example 271[2-(4-Chlororophenoxymethyl)-6-methyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIId-15):

MS 330.2 (M+H)⁺

Example 272[2-(4-Chlororophenoxymethyl)-6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIId-16):

white solid; ¹H NMR (DMSO) δ2.20 (3H, s), 3.43 (3H, s), 4.49 (2H, s),5.20 (2H, s), 6.05 (1H, br), 7.05 (2H, d), 7.33 (2H, d), 10.55 (1H, br);MS 360.2 (M+H)⁺

Example 273[2-(4-Chlororophenoxymethyl)-6-methyl-pyrimidin-4-yl]-[5-(furan-2-yl)-2H-pyrazol-3-yl]-amine(IIId-17):

MS 382.2 (M+H)⁺

Example 274(5-Methyl-2H-pyrazol-3-yl)-(2-phenylsulfanylmethyl-5,6,7,8-tetrahydro-quinazolin-4-yl)-amine(IId-7):

MS 352.5 (M+H)⁺

Example 275[2-(4-Methylphenylsulfanylmethyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IId-8):

MS 380.2 (M+H)⁺

Example 276[2-(1-Methyl-1-phenyl-ethyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IId-9):

MS 362.3 (M+H)⁺

Example 277[2-(2,6-Dichlorobenzyl)-5,6,7,8-tetrahydro-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IId-10):

MS 388.1 (M+H)⁺

Example 278[7-Benzyl-2-(2,6-dichlorobenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IId-11):

MS 479.5 (M+H)⁺

Example 279[6-Benzyl-2-(4-chlorophenoxymethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IId-12):

MS 461.2 (M+H)⁺

Example 280[2-(4-Chlorophenoxymethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IId-13):

MS 371.3 (M+H)⁺

Example 281[2-(2,6-Dichlorobenzyl)-6-methyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIId-18):

MS 348.1 (M+H)⁺

Example 282[2-(2,6-Dichlorobenzyl)-5,6-dimethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIId-19):

white solid; ¹H NMR (DMSO) δ8.50 (1H, s), 7.70 (1H, d), 7.3-7.1 (3H, m),5.25 (1H, s), 4.10 (1H, s), 2.30 (3H, s), 2.10 (3H, s), 1.80 (3H, s); MS362.1 (M+H)⁺

Example 283(1H-Indazol-3-yl)-[2-(2-phenyl-cyclopropyl)-quinazolin-4-yl]-amine(IId-16):

¹HNMR (DMSO) 13.2(1H, s), 12.0(1H, s), 8.76(1H, m), 8.10(1H, m),7.85(2H, m), 7.75(1H, m), 7.61(1H, m) 7.41(1H, m), 7.30(2H, m), 7.20(2H,m), 7.12(2H, m), 2.35(2H, m), 1.60(1H, m), 1.35(1H, m); MS: m/z, 378.1MH+; HPLC R_(t)=3.21 min.

Example 284(7-Fluoro-1H-indazol-3-yl)-[2-(2-phenyl-cyclopropyl)-quinazolin-4-yl]-amine(IId-17):

¹HNMR (DMSO) 13.8(1H, s), 12.05(1H, s), 8.75(1H, m), 8.10(1H, m),7.85(2H, m), 7.60(1H, m), 7.35(3H, m) 7.25-7.10(4H, m), 2.35(2H, m),1.60(1H, m), 1.35(1H, m); MS: m/z, 396.1 MH+; HPLC R_(t)=3.26 min.

Example 285(5-Fluoro-1H-indazol-3-yl)-[2-(2-phenyl-cyclopropyl)-quinazolin-4-yl]-amine(IId-18):

¹HNMR (DMSO) 13.3(1H, s), 12.0(1H, s), 8.75(1H, m), 8.10(1H, m),7.85(2H, m), 7.65(2H, m), 7.35(3H, m) 7.20(1H, m), 7.10(2H, m) 2.40 (2H,m), 1.65(1H, m), 1.35(1H, m); MS: m/z, 396.1 MH+; HPLC R_(t)=3.26 min.

Example 286(5-Methyl-1H-pyrazol-3-yl)-[2-(2-phenyl-cyclopropyl)-quinazolin-4-yl]-amine(IId-19):

¹HNMR (DMSO) 12.8 (1H, s), 11.90(1H, s), 8.80(1H, m), 8.10(1H, m),7.85(2H, m), 7.30-7.20(5H, m), 6.55 (1H, s) 2.80 (1H, m), 2.55(1H, m),2.35 (3H,s) 2.00(2H, m); MS: m/z, 342.1 MH+; HPLC R_(t)=3.13 min.

Biological Testing

The activity of the compounds as protein kinase inhibitors may beassayed in vitro, in vivo or in a cell line. In vitro assays includeassays that determine inhibition of either the phosphorylation activityor ATPase activity of the activated protein kinase. Alternate in vitroassays quantitate the ability of the inhibitor to bind to the proteinkinase. Inhibitor binding may be measured by radiolabelling theinhibitor prior to binding, isolating the inhibitor/protein kinasecomplex and determining the amount of radiolabel bound. Alternatively,inhibitor binding may be determined by running a competition experimentwhere new inhibitors are incubated with the protein kinase bound toknown radioligands.

Biological Testing Example 1 K_(i) Determiniation for the Inhibition ofGSK-3

Compounds were screened for their ability to inhibit GSK-3β (AA 1-420)activity using a standard coupled enzyme system (Fox et al. (1998)Protein Sci. 7, 2249). Reactions were carried out in a solutioncontaining 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 300 μM NADH,1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were20 μM ATP (Sigma Chemicals, St Louis, Mo.) and 300 μM peptide(HSSPHQS(PO₃H₂)EDEEE, American Peptide, Sunnyvale, Calif.). Reactionswere carried out at 30° C. and 20 nM GSK-3β. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactatedehydrogenase.

An assay stock buffer solution was prepared containing all of thereagents listed above with the exception of ATP and the test compound ofinterest. The assay stock buffer solution (175 μl) was incubated in a 96well plate with 5 μl of the test compound of interest at finalconcentrations spanning 0.002 μM to 30 μM at 30° C. for 10 min.Typically, a 12 point titration was conducted by preparing serialdilutions (from 10 mM compound stocks) with DMSO of the test compoundsin daughter plates. The reaction was initiated by the addition of 20 μlof ATP (final concentration 20 μM). Rates of reaction were obtainedusing a Molecular Devices Spectramax plate reader (Sunnyvale, Calif.)over 10 min at 30° C. The K_(i)values were determined from the rate dataas a function of inhibitor concentration.

The following compounds were shown to have K_(i) values less than 0.1 μMfor GSK-3: IIa-2, IIa-3, IIa-8, IIa-9, IIa-11, IIa-12, IIa-17, IIa-18,IIa-21 to IIa-24, IIa-26, IIa-28, IIa-30 through IIa-32, IIa-39, IIa-43,IIa-46, IIa-47, IIa-61, IIc-3, IIc-6, IIc-8, IIc-10 through IIc-12,IIc-15, IIc-18, IIc-20 through IIc-22, IIc-24, IIc-25, IIc-27, IIc-30through IIc-32, IIc-35 to IIc-39, IIc-42, IIc-53, IIc-61, IIc-67,IIc-77, IIc-78, IIb-1, IIb-3, IIb-5, IIb-8, IId-1, IIIa-2, IIIa-3,IIIa-6, IIIa-17, IIIa-18, IIIa-24, IIIa-27, IIIc-2 through IIIc-5,IIIc-9, IIIc-11, IIIc-12, IIIc-15, IIIc-18, IIIc-19, IIIc-21, IIIc-24,IIIb-1 through IIIb-6, IIIb-8 through IIIb-10, IIIb-13, IIIb-14,IIId-20, IIId-21, IId-14, and IId-19.

The following compounds were shown to have K_(i) values between 0.1 and1.0 μM for GSK-3: IIa-1, IIa-4, IIa-5, IIa-7, IIa-14, IIa-15, IIa-20,IIa-29, IIa-34 through IIa-36, IIa-38, IIa-41, IIa-42, IIa-48, IIa-54,IIa-55, IIa-62, IIa-63, IIa-66, IIa-69, IIa-78, IIc-1, IIc-2, IIc-4,IIc-5, IIc-7, IIc-9, IIc-13, IIc-14, IIc-16, IIc-17, IIc-19, IIc-23,IIc-26, IIc-28, IIc-29, IIc-33, IIc-34, IIc-40, IIc-41, IIc-43 throughIIc-45, IIc-47 through IIc-52, IIc-54 through IIc-57, IIc-59, IIc-63through IIc-66, IIc-72, IIc-75, IIc-76, IIc-79, IIc-6, IIb-7, IIb-9,IId-2, IId-5, IId-6, IIIa-l, IIIa-4, IIIa-5, IIIa-7, IIIa-8, IIIa-10,IIIa-11, IIIa-19, IIIa-22, IIIa-23, IIIa-26, IIIa-29, IIIa-30, IIIa-31,IIIa-33, IIIa-34, IIIa-37, IIIa-42, IIIc-1, IIIc-8, IIIc-20, IIIc-23,IIIb-7, IIIb-11, IIIb-12, IIIb-15, IIIb-16, IId-16, IId-17, and IId-18.

The following compounds were shown to have K_(i) values between 1.0 and7.0 μM for GSK-3: IIa-10, IIa-13, IIa-25, IIa-40, IIa-45, IIa-49, IIa-50through IIa-52, IIa-64, IIa-65, IIa-67, IIa-68, IIa-71, IIa-72, IIa-74,IIa-76, IIa-77, IIa-81, IIc-58, IIc-60, IIc-62, IIc-68 through IIc-71,IIc-74, IId-3, IId-4, IIIa-15, IIIa-16, IIIa-21, IIIa-28, IIIa-35,IIIa-36, IIIa-38, IIIa-41, IIIa-43, IIIa-45, IIIa-49, IIIc-10, III-16,IIIc-17, and IIIc-22.

Biological Testing Example 2 K_(i) Determination for the Inhibition ofAurora-2

Compounds were screened in the following manner for their ability toinhibit Aurora-2 using a standard coupled enzyme assay (Fox et al (1998)Protein Sci 7, 2249).

To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mMMgCl₂, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and800 μM peptide (LRRASLG, American Peptide, Sunnyvale, Calif.) was addeda DMSO solution of a compound of the present invention to a finalconcentration of 30 μM. The resulting mixture was incubated at 30 ° C.for 10 min. The reaction was initiated by the addition of 10 μL ofAurora-2 stock solution to give a final concentration of 70 nM in theassay. The rates of reaction were obtained by monitoring absorbance at340 nm over a 5 minute read time at 30° C. using a BioRad Ultramarkplate reader (Hercules, Calif.). The K_(i) values were determined fromthe rate data as a function of inhibitor concentration.

The following compounds were shown to have K_(i) values less than 0.1 μMfor Aurora-2: IIa-1 through IIa-18, IIa-21 through IIa-64, IIa-66,IIa-68, IIa-69, IIa-71 through IIa-78, IIa-81, IIc-1 through IIc-13,IIc-15 through IIc-44, IIc-46 through IIc-61, IIc-63 through IIc-65,IIc-67 through IIc-69, IIb-1 through IIb-9, IId-1 through IId-3, IIIa-1through IIIa-8, IIIa-10 through IIIa-13, IIIa-15 through IIIa-32,IIIa-36 through IIIa-41, IIIa-44 through IIIa-49, IIIc-1 through IIIc-5,IIIc-12, and IIIc-15.

The following compounds were shown to have K_(i) values between 0.1 and1.0 μM for Aurora-2: IIa-20, IIa-65, IIa-67, IIa-70, IIa-80, IIc-14,IIc-66, IId-5, IId-6, IIIa-14, IIIa-33 through IIIa-35, IIIc-9, IIIc-11,IIIb-1, IIIb-2, IIIb-7, IIIb-10 through IIIb-13, IIIb-15, IIIb-16, andIIId-20.

The following compounds were shown to have K_(i) values between 1.0 and10.0 μM for Aurora-2: IIa-10, IIc-71, IIc-75, IIc-76, IId-4, IIIa-42,IIIa-43, IIIc-10, IIIb-3-6, IIIb-8, IIIb-9, and IIIb-14.

Biological Testing Example 3 CDK-2 Inhibition Assay

Compounds were screened in the following manner for their ability toinhibit CDK-2 using a standard coupled enzyme assay (Fox et al (1998)Protein Sci 7, 2249).

To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mMMgCl₂, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP, and100 μM peptide (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale, Calif.)was added a DMSO solution of a compound of the present invention to afinal concentration of 30 μM. The resulting mixture was incubated at 30°C. for 10 min.

The reaction was initiated by the addition of 10 μL of CDK-2/Cyclin Astock solution to give a final concentration of 25 nM in the assay. Therates of reaction were obtained by monitoring absorbance at 340 nm overa 5-minute read time at 30° C. using a BioRad Ultramark plate reader(Hercules, Calif.). The K_(i) values were determined from the rate dataas a function of inhibitor concentration.

The following compounds were shown to have K_(i) values less than 1 μMfor CDK-2: IIa-14, IIa-36, IIc-15, IIc-25, IIc-27, IIc-32, IIc-53, andIIIc-4.

The following compounds were shown to have K_(i) values between 1.0 and20.0 μM for CDK-2: IIa-38, IIa-40, IIa-44, IIa-52, and IIa-54.

Biological Testing Example 4 ERK Inhibition Assay

Compounds were assayed for the inhibition of ERK2 by aspectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7,2249). In this assay, a fixed concentration of activated ERK2 (10 nM)was incubated with various concentrations of the compound in DMSO (2.5%) for 10 min. at 30° C. in 0.1 M HEPES buffer, pH 7.5, containing 10 mMMgCl₂, 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg/mL pyruvatekinase, 50 μg/mL lactate dehydrogenase, and 200 μM erktide peptide. Thereaction was initiated by the addition of 65 μM ATP. The rate ofdecrease of absorbance at 340 nM was monitored. The IC₅₀ was evaluatedfrom the rate data as a function of inhibitor concentration.

The following compounds were shown to have K_(i) values less than 1 μMfor ERK-2: IIc-15, IIc-27, IIc-32, IIc-53, and IIIc-4.

The following compounds were shown to have K_(i) values between 1.0 and20.0 μM for ERK-2: IIc-18, IIc-25, and IIa-36.

Biological Testing Example 5 AKT Inhibition Assay

Compounds were screened for their ability to inhibit AKT using astandard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7,2249). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mMMgCl2, 25 mM NaCl , 1 mM DTT and 1.5% DMSO. Final substrateconcentrations in the assay were 170 μM ATP (Sigma Chemicals) and 200 μMpeptide (RPRAATF, American Peptide, Sunnyvale, Calif.). Assays werecarried out at 30 ° C. and 45 nM AKT. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ML pyruvate kinase and 10 μg/ml lactatedehydrogenase.

An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of AKT, DTT, and the testcompound of interest. 56 μl of the stock solution was placed in a 384well plate followed by addition of 1 μl of 2 mM DMSO stock containingthe test compound (final compound concentration 30 μM). The plate waspreincubated for about 10 minutes at 30° C. and the reaction initiatedby addition of 10 μl of enzyme (final concentration 45 nM) and 1 mM DTT.Rates of reaction were obtained using a BioRad Ultramark plate reader(Hercules, Calif.) over a 5 minute read time at 30° C. Compounds showinggreater than 50% inhibition versus standard wells containing the assaymixture and DMSO without test compound were titrated to determine IC₅₀values.

The following compounds were shown to have K_(i) values between 1.0 and20.0 μM for AKT-3: IIc-18, IIc-22, IIc-25, IIc-27, IIc-31, IIc-32,IIc-37, IIc-39, IIc-42, and IIc-53.

Biological Testing Example 6 SRC Inhibition Assay

The compounds were evaluated as inhibitors of human Src kinase usingeither a radioactivity-based assay or spectrophotometric assay.

Src Inhibition Assay A: Radioactivity-based Assay

The compounds were assayed as inhibitors of full length recombinanthuman Src kinase (from Upstate Biotechnology, cat. no. 14-117) expressedand purified from baculo viral cells. Src kinase activity was monitoredby following the incorporation of ³³P from ATP into the tyrosine of arandom poly Glu—Tyr polymer substrate of composition, Glu:Tyr=4:1(Sigma, cat. no. P-0275). The following were the final concentrations ofthe assay components: 0.05 M HEPES, pH 7.6, 10 mM MgCl₂, 2 mM DTT, 0.25mg/ml BSA, 10 μM ATP (1-2 μCi ³³P-ATP per reaction), 5 mg/ml polyGlu—Tyr, and 1-2 units of recombinant human Src kinase. In a typicalassay, all the reaction components with the exception of ATP werepre-mixed and aliquoted into assay plate wells. Inhibitors dissolved inDMSO were added to the wells to give a final DMSO concentration of 2.5%.The assay plate was incubated at 30° C. for 10 min before initiating thereaction with ³³P-ATP. After 20 min of reaction, the reactions werequenched with 150 μl of 10% quenched samples were then transferred to a96-well filter plate (Whatman, UNI-Filter GF/F Glass Fiber Filter, catno. 7700-3310) installed on a filter plate vacuum manifold. Filterplates were washed four times with 10% TCA containing 20 mM Na₃PO₄ andthen 4 times with methanol. 200 μl of scintillation fluid was then addedto each well. The plates were sealed and the amount of radioactivityassociated with the filters was quantified on a TopCount scintillationcounter. The radioactivity incorporated was plotted as a function of theinhibitor concentration. The data was fitted to a competitive inhibitionkinetics model to get the K_(i) for the compound.

Src Inhibition Assay B: Spectrophotometric Assay

The ADP produced from ATP by the human recombinant Src kinase-catalyzedphosphorylation of poly Glu—Tyr substrate was quanitified using acoupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In thisassay one molecule of NADH is oxidised to NAD for every molecule of ADPproduced in the kinase reaction. The disappearance of NADH can beconveniently followed at 340 nm.

The following were the final concentrations of the assay components:0.025 M HEPES, pH 7.6, 10 mM MgCl2, 2 mM DTT, 0.25 mg/ml poly Glu—Tyr,and 25 nM of recombinant human Src kinase. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,200 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactatedehydrogenase.

In a typical assay, all the reaction components with the exception ofATP were pre-mixed and aliquoted into assay plate wells. Inhibitorsdissolved in DMSO were added to the wells to give a final DMSOconcentration of 2.5%. The assay plate was incubated at 30° C. for 10min before initiating the reaction with 100 μM ATP. The absorbancechange at 340 nm with time, the rate of the reaction, was monitored on amolecular devices plate reader. The data of rate as a function of theinhibitor concentration was fitted to competitive inhibition kineticsmodel to get the K_(i) for the compound.

The following compounds were shown to have a K_(i) value of <100 nM onSRC: IIa-8, IIa-21, IIa-23, IIa-24, IIa-27, IIa-28, IIa-30 throughIIa-33, IIb-1, IIb-4, IIb-5, IIc-3, IIc-8, IIc-10, IIc-13, IIc-15,IIc-18, IIc-19, IIc-21 through IIc-24, IIc-31 through IIc-35, IIc-37through IIc-39, IIc-41 through IIc-44, IIc-51, IId-1, IId-2, IIIa-1,IIIa-6 through IIIa-8, IIIa-26 through IIIa-30, and IIIc-1 throughIIIc-5.

The following compounds were shown to have a K_(i) value of between 100nM and 1 μM for SRC: IIa-1, IIa-2, IIa-7, IIa-9, IIa-12, IIa-14, IIa-22,IIa-25, IIa-26, IIa-29, IIa-34 through IIa-42, IIa-46, IIa-47, IIa-49through IIa-52, IIa-56, IIa-57, IIa-59, IIa-61, IIa-62, IIa-66, IIa-67,IIa-69, IIa-72, IIa-73, IIa-75, IIb-6, IIb-8, IIc-4 through IIc-7,IIc-9, IIc-11, IIc-12, IIc-14, IIc-16, IIc-17, IIc-20, IIc-25 throughIIc-30, IIc-36, IIc-40, IIc-46 through IIc-50, IIc-52 through IIc-61,IIc-63 through IIc-65, IIc-67, IIc-69, IId-3, IIIa-2 through IIIa-5,IIIa-11, IIIa-14 through IIIa-18, IIIa-22 through IIIa-24, IIIa-31,IIIa-33, IIIa-35, IIIa-38 through IIIa-43, and IIIa-47.

The following compounds were shown to have a K_(i) value of between 1 μMand 6 μM for SRC: IIa-13, IIa-20, IIa-44, IIa-45, IIa-48, IIa-54,IIa-55, IIa-63, IIa-65, IIa-68, IIa-70, IIa-71, IIa-74, IIa-77, IIa-78,IIa-81, IIb-3, IIb-9, IIc-1, IIc-2, IIc-66, IIc-68, IIIa-13, IIIa-21,IIIa-25, IIIa-34, IIIa-36, IIIa-37, and IIIa-44.

While we have presented a number of embodiments of this invention, it isapparent that our basic construction can be altered to provide otherembodiments which utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments which have been represented by way of example.

We claim:
 1. A compound of formula IIa:

or a pharmaceutically acceptable salt thereof, wherein; R^(x) and R^(y)are taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ringheteroatoms selected from oxygen, sulfur, or nitrogen, wherein eachsubstitutable ring carbon of said fused ring formed by R^(x) and R^(y)is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴; R¹ is T-(Ring D); Ring D is a 5-7membered monocyclic ring or 8-10 membered bicyclic ring selected fromaryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl orheterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen,oxygen or sulfur, wherein each substitutable ring carbon of Ring D isindependently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴; T is a valence bond or a C₁₋₄alkylidene chain; Z is a C₁₋₄alkylidene chain; L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)S)₂—, —SO₂N(R⁶)—,—N(R⁶)—, —CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—,—N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R₆)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—; R²and R^(2′) are independently selected from —R, —T—W—R⁶, or R² and R^(2′)are taken together with their intervening atoms to form a fused, 5-8membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R^(2′) isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴; R³ is selected from —R, -halo, —OR,—C(═O)R, —CO₂R, —COCOR, —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR,—N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂,—N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or each R is independently selected fromhydrogen or an optionally substituted group selected from C₁₋₆aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ring atoms, or aheterocyclyl ring having 5-10 ring atoms; each R⁴ is independentlyselected from —R⁷, —COR⁷, —CO₂ (optionally substituted C₁₋₆ aliphatic),—CON(R⁷)₂, or —SO₂R⁷; each R⁵ is independently selected from —R, halo,—OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂,—CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionallysubstituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR,—N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or V is —O—, —S—, —SO—,—SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—, —CO₂—, —N(R⁶)CO—,—N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—,—C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—,—C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—,—C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—; W is —C(R⁶)₂O—,—C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—,—C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—; each R⁶ isindependently selected from hydrogen or an optionally substituted C₁₋₄aliphatic group, or two R⁶ groups on the same nitrogen atom are takentogether with the nitrogen atom to form a 5-6 membered heterocyclyl orheteroaryl ring; and each R⁷ is independently selected from hydrogen oran optionally substituted C₁₋₆ aliphatic group, or two R⁷ on the samenitrogen are taken together with the nitrogen to form a 5-8 memberedheterocyclyl or heteroaryl ring.
 2. The compound according to claim 1,wherein said compound has one, two, three, four, or all featuresselected from the group consisting of: (a) R^(x) and R^(y) are takentogether with their intervening atoms to form a fused, unsaturated orpartially unsaturated, 5-6 membered ring having 0-2 heteroatoms selectedfrom oxygen, sulfur, or nitrogen, wherein each substitutable ring carbonof said fused ring formed by R^(x) and R^(y) is independentlysubstituted by oxo, T—R³, or L—Z—R³, and each substitutable ringnitrogen of said ring formed by R^(x) and R^(y) is independentlysubstituted by R⁴; (b) R¹ is T-(Ring D), wherein T is a valence bond ora methylene unit; (c) Ring D is a 5-7 membered monocyclic ring or an8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;(d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen; or R² and R^(2′) aretaken together to form an optionally substituted benzo ring; and (e) R³is selected from —R, -halo, —OR, or —N(R⁴)₂.
 3. The compound accordingto claim 2, wherein: (a) R^(x) and R^(y) are taken together with theirintervening atoms to form a fused, unsaturated or partially unsaturated,5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur,or nitrogen, wherein each substitutable ring carbon of said fused ringformed by R^(x) and R^(y) is independently substituted by oxo, T—R³, orL—Z—R³, and each substitutable ring nitrogen of said ring formed byR^(x) and R^(y) is independently substituted by R⁴; (b) R¹ is T-(RingD), wherein T is a valence bond or a methylene unit; (c) Ring D is a 5-7membered monocyclic ring or an 8-10 membered bicyclic ring selected froman aryl or heteroaryl ring; (d) R² is —R or —T—W—R⁶ and R^(2′) ishydrogen; or R² and R^(2′) are taken together to form an optionallysubstituted benzo ring; and (e) R³ is selected from —R, -halo, —OR, or—N(R⁴)₂.
 4. The compound according to claim 2, wherein said compound hasone, two, three, or all features selected from the group consisting of:(a) R^(x) and R^(y) are taken together to form a benzo, pyrido,cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;(b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6membered monocyclic ring or an 8-10 membered bicyclic ring selected froman aryl or heteroaryl ring; (c) R² is —R and R^(2′) is hydrogen, whereinR is selected from hydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 memberedheteroaryl ring, or a 5-6 membered heterocyclic ring; and (d) R³ isselected from —R, -halo, —OR, or —N(R⁴)₂, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—.
 5. The compoundaccording to claim 4, wherein: (a) R^(x) and R^(y) are taken together toform a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno,piperidino, or imidazo ring; (b) R¹ is T-(Ring D), wherein T is avalence bond and Ring D is a 5-6 membered monocyclic ring or an 8-10membered bicyclic ring selected from an aryl or heteroaryl ring; (c) R²is —R and R^(2′) is hydrogen, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring; and (d) R³ is selected from —R, -halo, —OR, or—N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆ aliphatic, or 5-6membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is —O—,—S—, or —N(R⁴)—.
 6. The compound according to claim 4, wherein saidcompound has one, two, three, four, or all features selected from thegroup consisting of: (a) R^(x) and R^(y) are taken together to form abenzo, pyrido, piperidino, or cyclohexo ring; (b) R¹ is T-Ring D,wherein T is a valence bond and Ring D is a 5-6 membered aryl orheteroaryl ring; (c) R² is hydrogen or C₁₋₄ aliphatic and R^(2′) ishydrogen; (d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —NH—; and (e)Ring D is substituted by up to three substituents selected from -halo,—CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR,—C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂, —N(R⁴)SO₂R,—N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R₄)₂, or —N(R⁶)COCH₂CH₂CH₂N(R⁴)₂,wherein R is selected from hydrogen, C₁₋₆ aliphatic, phenyl, a 5-6membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
 7. Thecompound according to claim 6, wherein: (a) R^(x) and R^(y) are takentogether to form a benzo, pyrido, piperidino, or cyclohexo ring; (b) R¹is T—Ring D, wherein T is a valence bond and Ring D is a 5-6 memberedaryl or heteroaryl ring; (c) R² is hydrogen or C₁₋₄ aliphatic and R^(2′)is hydrogen; (d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —NH—; and (e)Ring D is substituted by up to three substituents selected from -halo,—CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR,—C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂, —N(R⁴)SO₂R,—N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or —N(R⁶)COCH₂CH₂CH₂N(R⁴)₂,wherein R is selected from hydrogen, C₁₋₆ aliphatic, phenyl, a 5-6membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
 8. Acompound selected from the group consisting of:(5-Methyl-2H-pyrazol-3-yl)-(2-phenylsulfanyl-quinazolin-4-yl)-amine;[2-(4-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2,4-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Methoxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2-Ethylphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;{2-[2,4-Bis(trifluoromethyl)phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2,3-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(3-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(1-Methylimidazol-2-ylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2-Hydroxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2,4-Difluorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(3,4-Dimethoxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(3-Methylphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2-Methoxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2-Naphthalenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2,6-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(3,4-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(Benzimidazol-2-ylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2-Aminophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenylsulfanyl-quinazolin-4-yl)-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methylphenylsulfanyl)-quinazolin-4-yl]-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxyphenylsulfanyl)-quinazolin-4-yl]-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dimethoxyphenylsulfanyl)-quinazolin-4-yl]-amine;[2-(3-Carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphtalen-2-ylsulfanyl)-quinazolin-4-yl]-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,4-difluorophenylsulfanyl)-quinazolin-4-yl]-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-ylsulfanyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,3-dichlorophenylsulfanyl)-quinazolin-4-yl]-amine;[2-(3-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine;[2-(2-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dimethylphenylsulfanyl)-quinazolin-4-yl]-amine;[2-(Benzimidazol-2-ylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-amine;[2-(4-Acetamido-phenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-1-ylsulfanyl)-quinazolin-4-yl]-amine;[2-(4-Acetamidophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Methanesulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamidophenylsulfanyl)-7-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamidophenylsulfanyl)-8-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3yl)-amine;[2-(4-Methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamidophenylsulfanyl)-8-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamidophenylsulfanyl)-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Bromophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(3-Bromophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Isopropanesulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Isobutyrylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;(5-Methyl-2H-pyrazol-3-yl)-[2-(4-propionylamino-phenylsulfanyl)-quinazolin-4-yl]-amine;[2-(4-cyclopropanecarbonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamido-phenylsulfanyl)-8-hydroxyquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamido-phenylsulfanyl)-7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(propane-1-sulfonylamino)-phenylsulfanyl]-quinazolin-4-yl}-amine;[2-(4-Ethylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamido-phenylsulfanyl)-7-hydroxyaminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Isobutanecarbonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-tert-Butoxycarbonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamido-phenylsulfanyl)-7-aminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(2-morpholin-4-yl-acetylamino)-phenylsulfanyl]-quinazolin-4-yl}-amine;(5-Cycloprpyl-2H-pyrazol-3-yl)-[2-(4-methylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-amine;[2-(4-Amino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamido-phenylsulfanyl)-quinazolin-4-yl]-(2H-pyrazol-3-yl)-amine;(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(4-morpholin-4-yl-butyrylamino)-phenylsulfanyl]-quinazolin-4-yl}-amine;(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(2-morpholin-4-yl-ethylcarbamoyl)-phenylsulfanyl]-quinazolin-4-yl}-amine;[8-Methoxy-2-(4-methylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;{2-[4-(2-Dimethylamino-ethylcarbamoyl)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine;{2-[4-(2-Dimethylamino-acetylamino)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine;[8-Hydroxy-2-(4-methylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;{2-[4-(3-Dimethylamino-propylcarbamoyl)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine;{2-[4-(3-Dimethylamino-propionylamino)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamido-phenylsulfanyl)-8-methoxy-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamidophenylsulfanyl)-8-(3-dimethylamino-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamidophenylsulfanyl)-7-(3-dimethylamino-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;(2-{4-[2-(tert-Butoxycarbonyl-methyl-amino)-acetylamino]-phenylsulfanyl}-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine;{2-[4-(2-Methylamino-acetylamino)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2Hpyrazol-3-yl)-amine;[2-(4-Acetamidophenylsulfanyl)-8-fluoro-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;and (1H-Indazol-3-yl)-(2-phenylsulfanyl-quinazolin-4-yl)-amine.
 9. Acomposition comprising a compound according to any one of claims 1-8,and a pharmaceutically acceptable carrier.
 10. The composition accordingto claim 9, further comprising an additional therapeutic agent selectedfrom an anti-proliferative agent or chemotherapeutic agent, an agent fortreating Alzheimer's Disease, an agent for treating for Parkinson'sDisease, an agent for treating Multiple Sclerosis (MS), an agent fortreating asthma, an anti-inflammatory agent, an immunomodulatory orimmunosuppressive agent, an agent for treating a neurological disorder,an agent for treating stroke, an agent for treating cardiovasculardisease, or an agent for treating diabetes.
 11. The compositionaccording to claim 9, wherein said composition is formulated foradministration to a human.
 12. A method of inhibiting Aurora-2, GSK-3,CDK-2, or Src activity in a biological sample comprising the step ofcontacting said biological sample with a compound according to any oneof claims 1-8.
 13. A method of inhibiting Aurora-2 activity in a patientcomprising the step of administering to said patient a compositionaccording to claim
 9. 14. A method of inhibiting Aurora-2 activity in apatient comprising the step of administering to said patient acomposition according to claim
 10. 15. A method of treating a disease ina patient, wherein said disease is selected from melanoma, lymphoma,neuroblastoma, leukemia, or a cancer selected from colon, breast, lung,kidney, ovary, pancreatic, renal, CNS, cervical, prostate, or cancer ofthe gastric tract said method comprising the step of administering tosaid patient a composition according to claim
 9. 16. The methodaccording to claim 15, wherein said method further comprisesadministering an additional therapeutic agent selected from achemotherapeutic agent or anti-proliferative agent.
 17. A method ofinhibiting GSK-3 in a patient comprising the step of administering tosaid patient a composition according to claim
 9. 18. A method ofinhibiting GSK-3 activity in a patient comprising the step ofadministering to said patient a composition according to claim
 10. 19. Amethod of treating a disease in a patient, wherein said disease isselected from diabetes, Alzheimer's disease, Huntington's Disease,Parkinson's Disease, AIDS-associated dementia, amyotrophic lateralsclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiomycetehypertrophy, reperfusion/ischemia or baldness, said method comprisingthe step of administering to said patient a composition according toclaim
 9. 20. The method according to claim 19, wherein said disease isdiabetes.
 21. A method of enhancing glycogen synthesis or lowering bloodlevels of glucose in a patient in need thereof, which method comprisesadministering to said patient a therapeutically effective amount of acomposition according to claim
 9. 22. A method of inhibiting theproduction of hyperphosphorylated Tau protein in a patient, which methodcomprises administering to a patient in need thereof a therapeuticallyeffective amount of a composition according to claim
 9. 23. A method ofinhibiting the phosphorylation of β-catenin, which method comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a composition according to claim
 9. 24. A method of inhibitingCDK-2 activity in a patient comprising the step of administering to saidpatient a composition according to claim
 9. 25. A method of inhibitingSrc activity in a patient comprising the step of administering to saidpatient a composition according to claim
 9. 26. A method of treating adisease in a patient wherein said disease is selected fromhypercalcemia, osteoporosis, osteoarthritis, symptomatic treatment ofbone metastasis, and Paget's disease which method comprisesadministering to said patient a therapeutically effective amount of acomposition according to claim 9.